|REVIEW ARTICLE: BIOMARKER SERIES
|Year : 2021 | Volume
| Issue : 3 | Page : 516-523
Biomarker series: KRAS- A narrative review
Ullas Batra1, Shrinidhi Nathany2
1 Department of Medical Oncology, Rajiv Gandhi Cancer Institute and Research Centre, Delhi, India
2 Department of Section of Molecular Diagnostics, Rajiv Gandhi Cancer Institute and Research Centre, Delhi, India
|Date of Submission||12-Aug-2021|
|Date of Decision||05-Sep-2021|
|Date of Acceptance||16-Sep-2021|
|Date of Web Publication||08-Oct-2021|
Sector 5, Rohini, Sir Chhotu Ram Marg, New Delhi - 110 085
Source of Support: None, Conflict of Interest: None
Non-small cell lung cancer (NSCLC) has emerged as the poster child of molecular medicine. Kirsten rat sarcoma (KRAS)-mutated NSCLC is a common yet heterogeneous entity with distinct clinical and prognostic characteristics. Therapeutically, targeting the KRAS mutation in NSCLC has been the most difficult challenge faced by scientists and drug developers and after decades of efforts, a final breakthrough in the form of KRAS G12C inhibitors has emerged. In this edition of the biomarker series, we review KRAS, its biology, clinical features, and the therapeutic options in KRAS-mutant NSCLC. We performed a thorough search in PubMed, Embase, and Scopus and finally included 59 articles to write this review.
Keywords: G12C, Kirsten rat sarcoma, sotorasib, KRAS
|How to cite this article:|
Batra U, Nathany S. Biomarker series: KRAS- A narrative review. Cancer Res Stat Treat 2021;4:516-23
| Introduction|| |
The last decade has seen a paradigm shift in the development of molecular targeted therapies which have ushered in a new era of precision and personalized medicine. Oncogenic mutations in genes such as FLT3, and IDH, and oncogenic fusions have been among the first targets to be discovered. Tumor suppressors still remain outside the purview of targeted therapy except BRCA genes. The rat sarcoma virus (RAS) family of genes has been commonly implicated in malignancies of the colon, lung, and pancreas, with Kirsten RAS (KRAS) viral oncogene homolog being the most frequent oncogenic mutation detected in non-small-cell lung carcinoma (NSCLC). KRAS accounts for almost 30% of cases of lung adenocarcinomas in the West and close to 10% in Asia, with KRAS G12C (glycine to cysteine substitution at codon 12 of KRAS) mutation being the most common., Recent developments in the understanding of biological heterogeneity and disease pathobiology have led to unprecedented hopes for precision medicine in this group of patients. Until very recently considered “undruggable” despite numerous efforts, KRAS has finally emerged as a molecular target with new drugs approved in this space, and many in the pipeline.
The aim of this review article is to describe the structure, and molecular biology of KRAS, and the clinical characteristics, along with the most recent advances in the therapeutic strategies in KRAS-mutant NSCLC.
| Methods|| |
This is a narrative review; we did not perform a meta-analysis or systematic analysis. Therefore, we did not apply specific inclusion/exclusion criteria to select articles for this review. The articles were identified by searching PubMed, EMBASE, Scopus, and My Cancer Genome, using the keywords “G12C,” “KRAS,” “NSCLC,” and “Sotorasib.” A total of 59 articles were finally included for preparing the review
| Historical Perspective|| |
The oncogenic ability of KRAS was discovered almost four decades ago, by Scolnick et al.and Scolnick and Parks, in their study on the nucleic acid structure of KRAS. The relationship of RAS and lung cancer was established later in 1984 by Malumbres and Barbacid in a landmark study demonstrating the presence of KRAS mutation in a specimen of lung, which was absent in normal lung tissue.
| Molecular Biology|| |
KRAS maps to the short arm of chromosome 12 (chr12p12.1). KRAS is a member of the RAS family of proteins which also includes Harvey RAS viral oncogene homolog and neuroblastoma RAS viral oncogene homolog. These proteins belong to the family of small guanosine triphosphatases and are intracellular guanine nucleotide-binding proteins. The structure comprises a catalytic domain (G domain) which is responsible for binding of guanine and activation of signaling, and a hypervariable C-terminal region which houses farnesyl or prenyl groups which are post-transcriptional modifications, and diverge in various isoforms to help in localization of the RAS proteins to the cell membranes.
The downstream signaling involves two alternative states of the RAS proteins, i.e., RAS-GTP which is the active form and RAS-GDP which is the inactive form. The active complex is involved in activation of several downstream pathway effectors such as Raf-MEK-ERK, PI3K-AKT-mTOR, and the RalGDS-RalA/B pathways. These pathways control multiple functions in the cell including cellular proliferation, apoptosis, cell motility, and survival. Constitutive activation of KRAS occurs by the binding of several growth factors to their receptors, including epidermal growth factor receptor (EGFR) which is the most relevant in lung cancer. Adaptor proteins act together with the intracellular domain of EGFR and recruit factors such as Son of Sevenless (SOS) where they combine with RAS to facilitate the exchange of GDP for GTP. RAS has an intrinsic GTPase activity by interaction with GTPase activating proteins and it causes hydrolysis of GTP to GDP, terminating the RAS signaling. Mutations in RAS molecules impair this intrinsic GTPase activity, thus locking it in an active GTP conformation, independent of the upstream signal. A schematic representation of the KRAS signaling is depicted in [Figure 1].
|Figure 1. Signaling of KRAS. GDP: Guanosine diphosphate, GTP: Guanosine triphosphate, TIAM1: Tumor invasion and metastasis inducing protein 1, RAC:Rho-like GTPase.|
Click here to view
Mutations and isoforms
KRAS4A and KRAS4B are two highly similar proteins located at the KRAS locus, and are the result of alternative splicing which leads to a structural difference only in their C-termini. 4B is ubiquitous in expression, whereas 4A is tissue-specific and is essential in lung cancer carcinogenesis.
Most mutations in KRAS occur in exons 2 and 3 of the gene. Missense mutations are the most commonly occurring genomic alterations, which can arise either due to transition (G>A) resulting in G12D and G13D mutations, or due to transversions (G>T or G>C) resulting in G12V and G12C mutations. The most frequent among these in NSCLC is the G12C occurring in ~50% of cases. Other mutations involving the Q61 and A146 codons have been rarely reported in NSCLC, however, are canonical in colorectal and pancreatic cancers. [Table 1] depicts the frequencies of different alterations in lung adenocarcinoma and squamous cell carcinoma in the Cancer Genome Atlas and the Memorial Sloan Kettering Cancer Center (MSKCC) cohorts.
|Table 1: Mutation specific frequencies in the Cancer Genome Atlas and Memorial Sloan Kettering Cancer Center primary lung adenocarcinoma cohorts and the Cancer Genome Atlas squamous cell carcinoma cohort|
Click here to view
| Clinical Characteristics|| |
KRAS mutations in NSCLC are associated with a distinct clinicodemographic patient profile, and are noted more commonly in female patients, smokers, and tumors with mucinous histology. KRAS mutations were detected in 22% cases in a cohort of 500 patients of lung adenocarcinomas from the MSKCC, New York, USA. The transversion mutations as described above have been found to be more common in ever-smokers when compared to the transition mutations which are more common in never-smokers. In the Lung Cancer Mutation Consortium Study on 1655 patients, 27% were found to harbor KRAS mutations, with the majority of patients (53%) being female and smokers (93%). This is in contrast to other commonly implicated biomarkers such as EGFR, ALK, and ROS1 which are more commonly altered in non-smokers. In an Indian study by Chandrani et al., involving 45 NSCLC patients, KRAS mutations were detected in 13% of cases. In another contemporary Indian study by Tripathi et al., among the 50 solid tumors that were noted to have KRAS mutation, 25 (50%) cases were of NSCLC. Considering squamous histology separately, 1.1% of cases in an Indian cohort were detected to harbor a KRAS mutation.
The presence of a mutation in KRAS has been found in many studies to have a negative impact on prognosis, whereas other researchers have reported no significant association with survival. In a meta-analysis of 53 studies, Mascaux et al. found that the presence of a KRAS mutation correlated with a worse prognosis (hazard ratio [HR] 1.40; P = 0.01). Contrary to this, Villaruz et al., in a study at Pittsburgh, USA, on 998 patients with lung adenocarcinomas, concluded that KRAS was not an individual prognostic factor. In a landmark study which involved a pooled analysis of four trials investigating the role of adjuvant chemotherapy in 1500 patients of mixed ethnicities with NSCLC, including 300 patients harboring KRAS-mutant tumors, the presence of KRAS mutation was found to be of no prognostic significance. Another study involving 1935 patients of mixed ethnicities with lung cancer found that patients with wild type KRAS had a clear overall survival (OS) advantage, whereas in the meta-analysis involving patients with different ethnic origins by Fan et al., the presence of KRAS mutation in circulating tumor DNA was associated with a shorter progression-free survival (PFS) and OS. In a study involving 6939 patients that compared the difference in survivals between patients belonging to different ethnic groups, the authors concluded that the HR for PFS in Asians was higher when compared to non-Asians with KRAS-mutant lung cancer, indicating a comparatively worse prognosis in the Asian KRAS-mutant cohort. There are no large-scale studies from the Indian subcontinent regarding the prognostic implications of KRAS mutations in lung cancer.
Heterogeneity exists within the different mutation subgroups of KRAS-mutated NSCLC. The G12V mutation has been reported to be associated with better response rates to chemotherapy and slightly longer PFS. This finding was corroborated by pre-clinical studies done by Garassino et al., who found that G12V-mutant tumor cells were more sensitive to cisplatin. They also demonstrated that the G12D mutation led to an increased resistance to paclitaxel but increased sensitivity to sorafenib. They also demonstrated that the presence of the G12C mutation was associated with a reduced response to cisplatin and increased sensitivity to paclitaxel and pemetrexed.
| Co-Occurring Genomic Alterations in Alterations in KRAS-Mutated NSCLC|| |
An important aspect of KRAS-mutant NSCLC is the presence of heterogeneity not only in the KRAS genomic loci but also due to frequently co-occurring genomic alterations. These include alterations in genes such as TP53 (39.4%), CDKN2A/2B, STK11 (19.8%), and KEAP1 (12.9%). These have been reported to have important implications on disease behavior as well as therapeutic vulnerabilities. Tumors with co-mutated STK11/KEAP1 show reduced responses to immune checkpoint inhibition when compared to the other two types (KRAS with TP53 shows good response, whereas KRAS with coexistent CDKN2A/2B shows an intermediate response to immunotherapy) described. There are also differences in the relapse-free survival when comparing the tumors that have TP53 with KRAS co-mutations and the others (KRAS with STK11/LKB1 and KRAS with CDKN2A/2B subgroups), with the former showing longer relapse-free survival when compared to the other two subgroups (KRAS with STK11/LKB1 and KRAS with CDKN2A/2B subgroups). Skoulidis et al. conducted an integrative study involving genomics, transcriptomics, and proteomics in KRAS-mutant NSCLC and found three distinct subsets defined by the presence of co-occurring alterations. These are depicted in [Table 2]. Other co-occurring alterations include MET amplification (15.4%), ERBB2 amplification (13.8%), EGFR (1.2%), and BRAF (1.2%). The interesting relationship between coexistent EGFR mutation with KRAS mutation has been studied widely. In a study by Noronha et al. and Choughule et al.,, KRAS sequencing was performed in 86 NSCLC patients; 18.6% had a coexistent KRAS mutation (15 were found to have a coexistent KRAS G12C and 1 patient harbored a G12V mutation). Three of the G12C mutant tumors harbored a deletion in exon 19 in EGFR and attained a partial response to EGFR TKI therapy. However, 12 of 13 patients who harbored a G12C mutation with wild-type EGFR, did not show a response to EGFR TKI. This implies that the presence of a KRAS mutation with EGFR wild-type status is not predictive of response to EGFR TKI therapy, and hence, selecting patients for EGFR TKI does not warrant KRAS testing in NSCLC. The same results have been corroborated in studies in the rest of the world.,
| Detection of KRAS Alterations|| |
Missense mutations are the most common alterations in most oncogenes; hence, KRAS alterations have been traditionally detected using simple polymerase chain reaction (PCR)-based techniques involving the allele-specific PCR, and real-time PCR. Direct sequencing using the Sanger technique and nowadays next-generation sequencing (NGS)-based panels are also being widely employed. Incorporation of KRAS testing in the new National Comprehensive Cancer Network guidelines for biomarker testing in second-line testing (after testing for EGFR, ALK, ROS1) for NSCLC, especially in smokers, has led to the emergence of liquid biopsy-based detection methods including Droplet Digital PCR as well as the Roche Cobas V2 platform. However, since the adequacy of tissue in cases of NSCLC is a major concern in modern-day molecular biology, KRAS has been incorporated into targeted as well as larger gene panels for use in NGS-based panels. These not only offer a higher throughput but also help determine the co-mutation profile which may have important therapeutic implications. A detailed description and comparison of various techniques used to detect KRAS mutation is depicted in [Table 3].,,,
| Therapeutic Options|| |
High affinity of RAS for GTP/GDP and high intracellular concentrations have been the main reasons for failure of in-vivo blockage of the catalytic site using competitive inhibitors. Hence, efforts in the past have mainly relied on indirect targeting of KRAS either using conventional cytotoxic chemotherapy or inhibition of other downstream effectors, as described earlier.,,
| Past efforts and results|| |
Results from the Phase III SELECT-1 trial showed that adding the MEK inhibitor, selumetinib, to docetaxel did not prolong the PFS when compared to chemotherapy alone in KRAS-mutant NSCLC; the reported median PFS was 3.9 months for the combination versus 2.8 months for docetaxel alone, (P = 0.44). Trametinib, another MEK1/2 inhibitor, did not result in an improved PFS or response rate when compared with docetaxel. The BASALT-1 study investigating the pan-PI3K inhibitor, buparlisib, was also stalled early due to disappointing interim results.
Two classes of cysteine 12 modifying inhibitors have been developed recently which bind to the KRAS nucleotide pocket. KRAS G12C is found in 3% of colorectal cancers, 13% of cases of all lung cancers, and in 50% of all KRAS-mutant NSCLC. In tumors that harbor the KRAS G12C mutation, the cysteine is located in a cryptic pocket in the GDP-KRAS, for which covalent inhibitors targeting this cryptic pocket have been developed, which, in turn, lead to allosteric inhibition of the 12-cysteine codon.
Direct KRAS G12C inhibitors
Sotorasib (AMG 510) is an orally active KRAS G12C inhibitor which permanently blocks the KRAS G12C in an inactive GDP-complex state. In the CodeBreaK100 trial, which investigated the efficacy of sotorasib in pre-treated solid tumors including colorectal and NSCLC, a disease control rate of 88.1% was achieved in patients with NSCLC and 73.8% in patients with colorectal cancer. The median PFS attained was 6.3 months in the patients with NSCLC, and 4 months for the patients with colorectal malignancies. It was also found to be safe with an acceptable toxicity profile; the common adverse events were diarrhea, fatigue, and nausea. Hong et al., in a phase I study of sotorasib in 129 patients with KRAS G12C-mutant NSCLC, demonstrated an objective response rate of 32% and a disease control rate of 88%. The median time to response was 1.4 months and the median duration of response was 10.9 months.
The results of the Phase II CodeBreaK100 study in 126 patients with advanced NSCLC who were KRAS G12C mutant were reported at the World Conference on Lung Cancer 2020. Of the total cohort of patients, 46 demonstrated a confirmed response resulting in an objective response rate of 37% and a disease control rate of 80%. The safety profile was excellent with no treatment-related deaths, and the most frequent Grade 3 adverse events noted were elevation of aminotransferases (11.9%) and diarrhea (4%). The Phase III CodeBreaK 200 trial (NCT04303780) which is comparing sotorasib with docetaxel in patients who have progressed on platinum-based chemotherapy and immune-checkpoint inhibitors is underway. In view of the promising results, on May 28, 2021, the United States Food and Drug Administration (US FDA) granted accelerated approval to sotorasib for use in patients with locally advanced and metastatic NSCLC with KRAS G12C mutation who have received at least one prior line of cancer-directed therapy. The FDA also approved two companion diagnostic tests - the Qiagen therascreen KRAS RGQ PCR kit and Guardant360 CDx for the detection of KRAS G12C in tissue and blood samples of patients, respectively. The recommended dose of sotorasib as per the FDA label is 960 mg once daily orally, with or without food. Sotorasib demonstrates a time-dependent kinetics, and the median time to reach peak plasma concentration is 1 hour. Consumption of fatty high-calorie foods has been shown to increase absorption by 25%. The metabolism is by non-enzymatic conjugation and through the cytochrome system, and the main route of excretion is in the feces (74%) and partly by renal excretion (6%).
This is another covalent G12C inhibitor developed by Mirati Therapeutics Inc. which binds to the cryptic pocket in GDP-KRAS, inhibiting the KRAS pathway. There were 110 patients of NSCLC, colorectal, pancreatic, ovarian, and endometrial tumors with KRAS G12C mutation enrolled in the KRYSTAL-1 study which investigated the efficacy and safety of adagrasib. The preliminary results were presented at the 32nd EORTC-NCI-AACR Symposium in 2020, in which among the 51 evaluable patients, the objective response rate was reported to be 45% and the disease control rate was 96%. It demonstrated a manageable safety profile with the most common Grade 3 events being diarrhea, nausea, vomiting, fatigue, and elevation of aminotransferases. The clinical trials on direct KRAS inhibitors are summarized in [Table 4]
Novel therapeutic approaches under investigation for KRAS-mutated tumors
Despite the success of the direct G12C inhibitors, many other novel therapeutic compounds targeting KRAS are under investigation. This is attributed to the fact that G12C mutation occurs in lower frequency in other malignancies, and numerous acquired resistance mechanisms to G12C inhibition have already been described which activate alternate RAS-dependent mechanisms. An overview of these approaches with the mechanisms of action is provided in [Table 5].
|Table 5: Novel therapeutic compounds and their mechanism of action which are under investigation for KRAS inhibition|
Click here to view
Synthetic lethal partners are genes which, if mutated alone, are compatible with viability; pharmacological inhibition of these causes cell death. Many potential synthetic lethal partners have been identified for KRAS which include BCL-XL, FGFR1, CDK4, AKT, XPO1, YAP1, WT1, and GATA2. Trials are evaluating novel mechanisms to inhibit these.
Autophagy is a cellular process resulting in degradation of the intracellular components. This process is stimulated by the unfolded protein response pathway, nutrient, and oxidative stress. The role of KRAS in this regard has been studied, and the use of hydroxychloroquine which causes inhibition of this process unfortunately failed to show therapeutic activity in patients of pancreatic cancer.
| Resistance Mechanisms to KRAS Inhibition|| |
Resistance mechanisms to KRAS G12C inhibition have been described. These include increased receptor tyrosine kinase activity which, in turn, promotes the cycling of G12C to its active form. Inactivity of other growth factor signals can also bypass the blockade leading to intrinsic G12C resistance. High basal EGFR activity, especially in colon cancers, leads to higher phosphorylated ERK and thus KRAS G12C resistance. Other mechanisms include reactivation of the MAPK pathway, PI3K-AKT activation, and activation of receptor tyrosine kinase signalling. Feedback reactivation of wild-type KRAS has also been demonstrated in G12C models. Additional alterations in KRAS including amplification also lead to G12C resistance. Aurora kinase A also promotes drug inhibition escape leading to G12C resistance. In view of these various intrinsic and adaptive resistance mechanisms, combination therapies are being tried in patients with KRAS G12C mutations for enhancing their clinical benefit in terms of survival outcomes and response rates.
| Role of Immunotherapy|| |
The role of KRAS as a predictive marker for immune checkpoint inhibition remains elusive. A subgroup analysis of CheckMate 057 showed that patients who had KRAS-mutant NSCLC had a superior clinical benefit with nivolumab when compared to docetaxel. A pooled analysis of five trials has also demonstrated superior outcomes in KRAS-mutant NSCLC when treated with immunotherapy in the second-line setting. In the IMMUNOTARGET study, these findings were corroborated, depicting a greater clinical benefit of immunotherapy in KRAS-mutant NSCLC when compared to EGFR-mutated NSCLC. However, the presence of co-occurring STK11 and KEAP1 mutations is a negative predictor for immunotherapy efficacy in KRAS-mutated tumors. A recent study demonstrated that sotorasib can potentiate immune rejection when used in combination with anti-programmed cell death 1 (PD1) drugs. This phase 1b trial (CodeBreaKTM 101, NCT04185883) is ongoing. In the KEYNOTE-042 study, patients with PD-ligand 1 (PD-L1)-positive advanced NSCLC were randomized to first-line pembrolizumab or platinum-based chemotherapy. It showed that patients with KRAS G12C mutation demonstrated a higher PD-L1 tumor proportion score and tumor mutation burden, compared with patients with KRAS wild-type NSCLC. However, synergistic association of KRAS G12C inhibitors with immune checkpoint inhibitors needs further investigation.
| Conclusions and Future Perspectives|| |
KRAS mutations are common across all malignancies including both solid tumors as well as hematolymphoid malignancies. A detailed knowledge of this is therefore essential not only for a better understanding of the disease process and the natural history but also for therapeutics and prognostics. CRISPR/Cas9-mediated technologies are being tried, as well as mRNA-based vaccines specifically targeting KRAS G12D/V are in trials (Phase I). An mRNA vaccine, mRNA-5671/V941, encoding G12D, G12V, G12C, and G13D as monotherapy or in combination with pembrolizumab is underway (NCT03948763). Overall, the future for patients with KRAS-mutant tumors looks brighter compared to failed past efforts, and further studies are needed for better elucidation of resistance mechanisms, and upcoming therapeutic approaches. The administration of immunotherapy/chemoimmunotherapy has been studied in many trials as discussed above, depicting reasonable outcomes in the KRAS-mutated subgroup, when compared to other oncogene addicted tumors.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Prior IA, Lewis PD, Mattos C. A comprehensive survey of ras mutations in cancer Ian. Cancer Res 2012;72:2457-67.
Dearden S, Stevens J, Wu YL, Blowers D. Mutation incidence and coincidence in non small-cell lung cancer: Meta-analyses by ethnicity and histology (mutMap). Ann Oncol 2013;24:2371-6.
Uras IZ, Moll HP, Casanova E. Targeting KRAS mutant non-small-cell lung cancer: Past, present and future. Int J Mol Sci 2020;21:1-30.
Chatterjee K, Mukherjee P, Hoque J, Das M, Saha S. Extended RAS mutations (KRAS and NRAS) in patients with colorectal cancers in eastern India : An observational study. Cancer Res Stat Treat 2021;4:244-50. [Full text]
Scolnick EM, Rands E, Williams D, Parks WP. Studies on the nucleic acid sequences of Kirsten sarcoma virus: A model for formation of a mammalian RNA-containing sarcoma virus. J Virol 1973;12:458-63.
Scolnick EM, Parks WP. Harvey sarcoma virus: A second murine type C sarcoma virus with rat genetic information. J Virol 1974;13:1211-9.
Malumbres M, Barbacid M. RAS oncogenes: The first 30 years. Nat Rev Cancer 2003;3:459-65.
Cserepes M, Ostoros G, Lohinai Z, Raso E, Barbai T, Timar J, et al
. Subtype-specific KRAS mutations in advanced lung adenocarcinoma : A retrospective study of patients treated with platinum-based chemotherapy subtype-specific KRAS mutations in advanced lung adenocarcinoma : A retrospective study of patients treated with p. Eur J Cancer 2014;50:1819-28.
Ferrer I, Zugazagoitia J, Herbertz S, John W, Paz-Ares L, Schmid-Bindert G. KRAS-mutant non-small cell lung cancer: From biology to therapy. Lung Cancer 2018;124:53-64.
Merz V, Gaule M, Zecchetto C, Cavaliere A, Casalino S, Pesoni C, et al.
Targeting KRAS: The elephant in the room of epithelial cancers. Front Oncol 2021;11:1-16.
Dogan S, Shen R, Ang DC, Johnson ML, D'Angelo SP, Paik PK, et al.
Molecular epidemiology of EGFR and KRAS mutations in 3,026 lung adenocarcinomas: Higher susceptibility of women to smoking-related KRAS-mutant cancers. Clin Cancer Res 2012;18:6169-77.
El Osta B, Behera M, Kim S, Berry LD, Sica G, Pillai RN, et al.
Characteristics and outcomes of patients with metastatic KRAS-mutant lung adenocarcinomas: The lung cancer mutation consortium experience. J Thorac Oncol 2019;14:876-89.
Chandrani P, Prabhash K, Prasad R, Sethunath V, Ranjan M, Iyer P, et al.
Drug-sensitive FGFR3 mutations in lung adenocarcinoma. Ann Oncol 2017;28:597-603.
Tripathi R, Nathany S, Mehta A, Batra U, Mattoo S, Sharma M. Malfeasance of KRAS mutations in carcinogenesis. Clin Exp Med 2021;21:439-45.
Joshi A, Mishra R, Desai S, Chandrani P, Kore H, Sunder R, et al.
Molecular characterization of lung squamous cell carcinoma tumors reveals therapeutically relevant alterations. Oncotarget 2021;12:578-88.
Mascaux C, Iannino N, Martin B, Paesmans M, Berghmans T, Dusart M, et al.
The role of RAS oncogene in survival of patients with lung cancer: A systematic review of the literature with meta-analysis. Br J Cancer 2005;92:131-9.
Villaruz LC, Socinski MA, Cunningham DE, Chiosea SI, Burns TF, Siegfried JM, et al.
The prognostic and predictive value of KRAS oncogene substitutions in lung adenocarcinoma. Cancer 2013;119:2268-74.
Shepherd FA, Domerg C, Hainaut P, Jänne PA, Pignon JP, Graziano S, et al.
Pooled analysis of the prognostic and predictive effects of KRAS mutation status and KRAS mutation subtype in early-stage resected non-small-cell lung cancer in four trials of adjuvant chemotherapy. J Clin Oncol 2013;31:2173-81.
Guan JL, Zhong WZ, An SJ, Yang JJ, Su J, Chen ZH, et al.
KRAS mutation in patients with lung cancer: A predictor for poor prognosis but not for EGFR-TKIs or chemotherapy. Ann Surg Oncol 2013;20:1381-8.
Fan Z, Fan K, Yang C, Huang Q, Gong Y, Cheng H. Critical role of KRAS mutation in pancreatic ductal adenocarcinoma. Transl Cancer Res 2018;7:1728-36.
Meng D, Yuan M, Li X, Chen L, Yang J, Zhao X, et al
. Prognostic value of K-RAS mutations in patients with non-small cell lung cancer: A systematic review with meta-analysis. Lung Cancer 2013;81:1-10.
Garassino MC, Marabese M, Rusconi P, Rulli E, Martelli O, Farina G, et al.
Different types of K-Ras mutations could affect drug sensitivity and tumour behaviour in non-small-cell lung cancer. Ann Oncol 2011;22:235-7.
Skoulidis F, Goldberg ME, Greenawalt DM, Hellmann MD, Awad MM, Gainor JF, et al. STK11/LKB1
mutations and PD-1 inhibitor resistance in KRAS-mutant lung adenocarcinoma. Cancer Discov 2018;8:822-35.
Skoulidis F, Byers LA, Diao L, Papadimitrakopoulou VA, Tong P, Izzo J, et al.
Co-occurring genomic alterations define major subsets of KRAS-mutant lung adenocarcinoma with distinct biology, immune profiles, and therapeutic vulnerabilities. Cancer Discov 2015;5:860-77.
Noronha V, Prabhash K, Thavamani A, Chougule A, Purandare N, Joshi A, et al.
EGFR mutations in Indian lung cancer patients: Clinical correlation and outcome to EGFR targeted therapy. PLoS One 2013;8:e61561.
Choughule A, Sharma R, Trivedi V, Thavamani A, Noronha V, Joshi A, et al
. Coexistence of KRAS mutation with mutant but not wild-type EGFR predicts response to tyrosine-kinase inhibitors in human lung cancer. Br J Cancer 2014;111:2203-4.
Zhu CQ, da Cunha Santos G, Ding K, Sakurada A, Cutz JC, Liu N, et al.
Role of KRAS and EGFR as biomarkers of response to erlotinib in national cancer institute of Canada clinical trials group study BR.21. J Clin Oncol 2008;26:4268-75.
Roberts PJ, Stinchcombe TE, Der CJ, Socinski MA. Personalized medicine in non-small-cell lung cancer: Is KRAS a useful marker in selecting patients for epidermal growth factor receptor-targeted therapy? J Clin Oncol 2010;28:4769-77.
Barlesi F, Mazieres J, Merlio JP, Debieuvre D, Mosser J, Lena H, et al.
Routine molecular profiling of patients with advanced non-small-cell lung cancer: Results of a 1-year nationwide programme of the French cooperative thoracic intergroup (IFCT). Lancet 2016;387:1415-26.
Hinrichs JW, van Blokland WT, Moons MJ, Radersma RD, Radersma-van Loon JH, de Voijs CM, et al.
Comparison of next-generation sequencing and mutation-specific platforms in clinical practice. Am J Clin Pathol 2015;143:573-8.
Franklin WA, Haney J, Sugita M, Bemis L, Jimeno A, Messersmith WA. KRAS mutation: Comparison of testing methods and tissue sampling techniques in colon cancer. J Mol Diagn 2010;12:43-50.
Matsunaga M, Kaneta T, Miwa K, Ichikawa W, Fujita KI, Nagashima F, et al
. A comparison of four methods for detecting KRAS mutations in formalin-fixed specimens from metastatic colorectal cancer patients. Oncol Lett 2016;12:150-6.
Cox AD, Fesik SW, Kimmelman AC, Luo J, Der CJ. Drugging the undruggable RAS: Mission possible? Nat Rev Drug Discov 2014;13:828-51.
Indini A, Rijavec E, Ghidini M, Cortellini A, Grossi F. Targeting KRAS in solid tumors: Current challenges and future opportunities of novel KRAS inhibitors. Pharmaceutics 2021;13:653.
Jänne PA, van den Heuvel MM, Barlesi F, Cobo M, Mazieres J, Crinò L, et al.
Selumetinib plus docetaxel compared with docetaxel alone and progression-free survival in patients with KRAS-mutant advanced non-small cell lung cancer: The SELECT-1 randomized clinical trial. JAMA 2017;317:1844-53.
Blumenschein GR Jr., Smit EF, Planchard D, Kim DW, Cadranel J, De Pas T, et al
. A randomized phase II study of the MEK1/MEK2 inhibitor trametinib (GSK1120212) compared with docetaxel in KRAS-mutant advanced non-small-cell lung cancer (NSCLC)†. Ann Oncol 2015;26:894-901.
Vansteenkiste JF, Canon JL, De Braud F, Grossi F, De Pas T, Gray JE, et al.
Safety and efficacy of buparlisib (BKM120) in patients with PI3K pathway-activated non-small cell lung cancer: Results from the phase II BASALT-1 study. J Thorac Oncol 2015;10:1319-27.
Ostrem JM, Peters U, Sos ML, Wells JA, Shokat KM. K-Ras (G12C) inhibitors allosterically control GTP affinity and effector interactions. Nature 2013;503:548-51.
Hong DS, Clinical PI, Program T, Anderson TM, Fakih MG, Therapeutics E, et al
. KRASG12C inhibition with sotorasib in advanced solid tumors. N Engl J Med 2020;383:1207-17.
Li B, Skoulidis F, Falchook G, Sacher A, Velcheti V, Dy G, et al.
PS01.07 registrational phase 2 trial of sotorasib in KRAS p.G12C mutant NSCLC: First disclosure of the codebreak 100 primary analysis. J Thorac Oncol 2021;16:S61.
Fakih M, Desai J, Kuboki Y, Strickler JH, Price JT, Durm GA, et al.
CodeBreak 100: Activity of AMG 510, a novel small molecule inhibitor of KRASG12C, in patients with advanced colorectal cancer. J Clin Oncol 2020;38:4018.
Reck M, Spira A, Besse B, Wolf J, Skoulidis F, Borghaei H, et al.
CodeBreak 200: A phase III multicenter study of sotorasib (AMG 510), a KRAS (G12C) inhibitor, versus docetaxel in patients with previously treated advanced non-small cell lung cancer (NSCLC) harboring KRAS p.G12C mutation. Ann Oncol 2020;31 Suppl 4:S754-840.
Agarwal A, Pragya R, Khaddar S, Kapoor A. Sotorasib – an inhibitor of KRAS p.G12c mutation in advanced non-small cell carcinoma: A narrative drug review. Cancer Res Stat Treat 2021;4:524-28.
Desai J, Gan H, Barrow C, Jameson M, Atkinson V, Haydon A, et al.
Phase I, open-label, dose-escalation/dose-expansion study of lifirafenib (BGB-283), an RAF family kinase inhibitor, in patients with solid tumors. J Clin Oncol 2020;38:2140-50.
Jänne PA, Rybkin II, Spira AI, Riely GJ, Papadopoulos KP, Sabari JK, et al.
KRYSTAL-1: Activity and safety of adagrasib (MRTX849) in advanced/metastatic non–small-cell lung cancer (NSCLC) harboring KRAS G12C mutation. Eur J Cancer 2020;138:S1-2.
Corcoran RB, Cheng KA, Hata AN, Faber AC, Ebi H, Coffee EM, et al.
Synthetic lethal interaction of combined BCL-XL and MEK inhibition promotes tumor regressions in KRAS mutant cancer models. Cancer Cell 2013;23:121-8.
Puyol M, Martín A, Dubus P, Mulero F, Pizcueta P, Khan G, et al
. A synthetic lethal interaction between K-Ras oncogenes and Cdk4 unveils a therapeutic strategy for non-small cell lung carcinoma. Cancer Cell 2010;18:63-73.
Aguirre AJ, Hahn WC. Synthetic lethal vulnerabilities in KRAS-mutant cancers. Cold Spring Harb Perspect Med 2018;8:1-18.
Chude CI, Amaravadi RK. Targeting autophagy in cancer: Update on clinical trials and novel inhibitors. Int J Mol Sci 2017;18:E1279.
Lito P, Solomon M, Li LS, Hansen R, Rosen N. Allele-specific inhibitors inactivate mutant KRAS G12C by a trapping mechanism. Science 2016;351:604-8.
Amodio V, Yaeger R, Arcella P, Cancelliere C, Lamba S, Lorenzato A, et al.
EGFR blockade reverts resistance to KRASG12C
inhibition in colorectal cancer. Cancer Discov 2020;10:1129-39.
Misale S, Fatherree JP, Cortez E, Li C, Bilton S, Timonina D, et al.
KRAS G12C NSCLC models are sensitive to direct targeting of KRAS in combination with PI3K inhibition. Clin Cancer Res 2019;25:796-807.
Ryan MB, Fece de la Cruz F, Phat S, Myers DT, Wong E, Shahzade HA, et al.
Vertical pathway inhibition overcomes adaptive feedback resistance to KRASG12C
inhibition. Clin Cancer Res 2020;26:1617-43.
Xue JY, Zhao Y, Aronowitz J, Mai TT, Vides A, Kim D, et al.
Rapid non-uniform adaptation to conformation-specific KRASG12C inhibition. Nature 2020;577:421-5.
Borghaei H, Paz-Ares L, Horn L, Spigel DR, Steins M, Ready NE, et al
. Nivolumab versus docetaxel in advanced non-squamous non- small cell lung cancer. New 2015;373:1627-39.
Yang H, Liang SQ, Schmid RA, Peng RW. New horizons in KRAS-mutant lung cancer: Dawn after darkness. Front Oncol 2019;9:1-13.
Mazieres J, Drilon A, Lusque A, Mhanna L, Cortot AB, Mezquita L, et al.
Immune checkpoint inhibitors for patients with advanced lung cancer and oncogenic driver alterations: Results from the IMMUNOTARGET registry. Ann Oncol 2019;30:1321-8.
Mok TS, Wu YL, Kudaba I, Kowalski DM, Cho BC, Turna HZ, et al.
Pembrolizumab versus chemotherapy for previously untreated, PD-L1-expressing, locally advanced or metastatic non-small-cell lung cancer (KEYNOTE-042): A randomised, open-label, controlled, phase 3 trial. Lancet 2019;393:1819-30.
A Phase 1, Open-Label, Multicenter Study to Assess the Safety and Tolerability of mRNA-5671/V941 as a Monotherapy and in Combination with Pembrolizumab in Participants with KRAS Mutant Advanced or Metastatic Non-Small Cell Lung Cancer, Colorectal Cancer o. Available from: https://clinicaltrials.gov/ct2/show/NCT03948763
. [Last accessed on 2021 Sep 15].
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]