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Table of Contents
LETTER TO THE EDITOR
Year : 2021  |  Volume : 4  |  Issue : 4  |  Page : 789-790

From bench to bedside and beyond: Challenges in direct KRAS targeting


Department of Pathology, All India Institute of Medical Sciences, New Delhi, India

Date of Submission29-Oct-2021
Date of Decision06-Nov-2021
Date of Acceptance09-Nov-2021
Date of Web Publication29-Dec-2021

Correspondence Address:
Deepali Jain
Department of Pathology, All India Institute of Medical Sciences, New Delhi - 110 029
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/crst.crst_248_21

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How to cite this article:
Gheware AP, Rathor A, Jain D. From bench to bedside and beyond: Challenges in direct KRAS targeting. Cancer Res Stat Treat 2021;4:789-90

How to cite this URL:
Gheware AP, Rathor A, Jain D. From bench to bedside and beyond: Challenges in direct KRAS targeting. Cancer Res Stat Treat [serial online] 2021 [cited 2022 Aug 20];4:789-90. Available from: https://www.crstonline.com/text.asp?2021/4/4/789/334193



With great interest and pleasure, we read the latest reviews on KRAS mutations in non-small-cell lung cancer (NSCLC) by Batra and Nathany and Agrawal et al.[1],[2] The authors have highlighted the recent advances in KRAS oncogenic biology, its clinical features, and therapeutic possibilities in NSCLC. In particular, they have emphasized how targeting specific KRAS mutations is becoming clinically relevant, by detailing sotorasib's direct allosteric irreversible inhibition of KRAS G12C, which recently led to an accelerated approval by the United States Food and Drug Administration.[2] However, there are still many challenges ahead, the most difficult of which is overcoming therapeutic resistance caused by acquired mutations in KRAS, phenotypic switching, and tumor plasticity to achieve long-term clinical benefit. This is attributed to the fact that other targeted therapies against aberrant EGFR and ALK genes have comparable outcomes.

Therefore, even though the direct targeting approach is clinically effective, it is necessary to discuss the obvious obstacles and possibilities that will arise as a result of the strong selection pressure applied to genetically unstable cancer cells. It may be more relevant to target the malignant features, such as immunometabolic dysfunction of KRAS-mutant cancers, rather than the protein itself. The difficulty in this scenario will be to overcome the compensatory mechanism that allows emancipation from the initial dependence, as evidenced by the presence of distinct routes to the KRAS-mutant lung cancer endotype.[3],[4] In this context, investigating an effective drug combination may be an option. For example, it will be worthwhile to examine a combination of drugs that target KRAS mutations and the immunosuppressive microenvironment, because KRAS-mutant lung cancer is more prevalent among smokers, and tobacco-induced tumors have a higher mutational and neoantigen burden. Furthermore, 50% of responders to programmed cell death-1 inhibitors have a KRAS mutation, compared to only 1 out of every 17 non-responders.[5] Yet, in the preclinical setting, the combination of KRAS inhibitors and immune checkpoint inhibitors demonstrated a synergistic effect;[3],[4] clinical trial results employing similar mechanisms are still awaited. Therefore, more research is warranted to test the drug combinations that can effectively eradicate cancer stem cells while eliciting a sustained response.

Moreover, to maximize the efficacy of KRAS targeted therapies, molecular stratification of KRAS-mutant tumors will be important. With the various emerging molecular pathways of KRAS-driven tumors being disclosed,[3],[6] it is critical to individualize therapy. The molecular profile of patients with lung cancer has been used to classify them and is crucial for the selection of appropriate patients to direct the therapies systematically.

Withal, it is critical to remember that we are only at the beginning of a very long road toward eradicating KRAS-mutant cancers. Nevertheless, these new paths provide promise for the field to be optimistic because they will almost certainly lead to new possibilities in clinical practice in the future.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Batra U, Nathany S. Biomarker series: KRAS – A narrative review. Cancer Res Stat Treat 2021;4:516-23.  Back to cited text no. 1
  [Full text]  
2.
Agrawal AK, Pragya R, Choudhary A, Gupta A, Sambasivaiah K, Mishra BK, et al. 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.  Back to cited text no. 2
  [Full text]  
3.
Salgia R, Pharaon R, Mambetsariev I, Nam A, Sattler M. The improbable targeted therapy: KRAS as an emerging target in non-small cell lung cancer (NSCLC). Cell Rep Med 2021;2:100186.  Back to cited text no. 3
    
4.
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;11:638360.  Back to cited text no. 4
    
5.
Rizvi NA, Hellmann MD, Snyder A, Kvistborg P, Makarov V, Havel JJ, et al. Cancer immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science 2015;348:124-8.  Back to cited text no. 5
    
6.
Kempf E, Rousseau B, Besse B, Paz-Ares L. KRAS oncogene in lung cancer: Focus on molecularly driven clinical trials. Eur Respir Rev 2016;25:71-6.  Back to cited text no. 6
    




 

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