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| LETTER TO THE EDITOR |
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| Year : 2021 | Volume
: 4
| Issue : 4 | Page : 790-791 |
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Batra et al.'s reply to Ventrapati and Gheware et al.
Ullas Batra1, Shrinidhi Nathany2, Himanshi Diwan2
1 Department of Medical Oncology, Rajiv Gandhi Cancer Institute and Research Centre, New Delhi, India
2 Department of Pathology (Molecular Diagnostics), Rajiv Gandhi Cancer Institute and Research Centre, New Delhi, India
| Date of Submission | 10-Nov-2021 |
| Date of Decision | 21-Nov-2021 |
| Date of Acceptance | 22-Nov-2021 |
| Date of Web Publication | 29-Dec-2021 |
Correspondence Address:
Ullas Batra
Department of Medical Oncology, Rajiv Gandhi Cancer Institute and Research Centre, New Delhi - 110 085
India
 Source of Support: None, Conflict of Interest: None
DOI: 10.4103/crst.crst_276_21
How to cite this article:
Batra U, Nathany S, Diwan H. Batra et al.'s reply to Ventrapati and Gheware et al. Cancer Res Stat Treat 2021;4:790-1 |
We thank Ventrapati[1] and Gheware et al.[2] for their critical appraisal and comments on our article, “Biomarker Series: KRAS—A narrative review.”[3] The Kirsten rat sarcoma virus (KRAS) oncogene has been widely studied and considered to be implicated in colorectal, lung, and pancreatic cancers. G12C (glycine to cysteine substitution at codon 12 of KRAS) is the most common KRAS point mutation observed in non-small-cell lung carcinoma (NSCLC).[4],[5] KRAS due to its physical structure and close affinity to guanosine-5'-triphosphate (GTP) in its active state was quite unfeasible to target.[6] Nevertheless, the development of sotorasib is indeed a sliver of hope.
We agree with Ventrapati[1] that sotarasib was given accelerated approval by the Food and Drug Administration as it was well tolerated and effective in patients with treatment-refractory NSCLC. However, we still have limited data for the same, and hence, further clinical trials will help unravel the path to targeted therapy for other KRAS-driven tumors like colorectal and pancreatic cancers. The effectiveness of sotorasib has been impressive in the CodeBreaK100 trial[7] among patients with NSCLC. The tumor response however was not as good in colorectal and pancreatic cancers, which can be attributed to the different primary driver mutations. Hence, more studies need to be conducted to explain the difference in tumor responses to sotarasib in NSCLC and other tumors with KRAS mutations.
We are in consensus with Ventrapati[1] in his concern regarding the reach and cost of the drug in a developing country like India, and we agree that united efforts by the government will be required to make this targetable drug available to a large set of patients.
We acquiesce in Gheware et al.'s[2] observation that due to various intrinsic and adaptive resistance mechanisms to KRAS G12C inhibition, an in-depth search of a combination of drugs should be executed to achieve better outcomes and survival rates in patients harboring KRAS mutations. KRAS-mutant NSCLCs are further categorized molecularly on the basis of proteomic data into three subtypes: KRAS with concomitant TP53 mutations, KRAS with inactivating mutation in the liver kinase b1, and KRAS with deletions of CDKN2A and CDKN2B.[8] These molecularly defined subgroups have distinctive responses to chemotherapy and immunotherapy. Nevertheless, we need to delve into more clinical trials possibly with combinations of drugs in these molecular subgroups to untangle the knots for better comprehension, as this could likely pave the path for better tailored therapies in future.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
| References | |  |
| 1. | Ventrapati P. Old targets, new bullets, nursing fresh hope. Cancer Res Stat Treat 2021;4:788-9.  [Full text] |
| 2. | Gheware A, Rathor A, Jain D. From bench to bedside and beyond: Challenges in direct KRAS targeting. Cancer Res Stat Treat 2021;4:789-90. [Full text] |
| 3. | Batra U, Nathany S. Biomarker series: KRAS – A narrative review. Cancer Res Stat Treat 2021;4:516-23. [Full text] |
| 4. | Uras IZ, Moll HP, Casanova E. Targeting KRAS mutant non-small-cell lung cancer: Past, present and future. Int J Mol Sci 2020;21:4325. |
| 5. | 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] |
| 6. | 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;4:524-8. |
| 7. | Hong DS, Fakih MG, Strickler JH, Desai J, Durm GA, Shapiro GI, et al. KRAS G12C inhibition with sotorasib in advanced solid tumors. N Engl J Med 2020;383:1207-17. |
| 8. | Hong DS, Kuo J, Sacher AG, Barlesi F, Besse B, Kuboki Y, et al. CodeBreak 100: Phase I study of AMG 510, a novel KRASG12C inhibitor, in patients (pts) with advanced solid tumors other than non-small cell lung cancer (NSCLC) and colorectal cancer (CRC). J Clin Oncol 2020;38:3511. |
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