KRAS Mutations in Cancer: Understanding Signaling Pathways to Immune Regulation and the Potential of Immunotherapy

Overview

Journal Cancers (Basel)

Publisher MDPI

Specialty Oncology

Date 2025 Mar 13

PMID 40075634

Authors

Priyanka Uniyal

Vivek Kumar Kashyap

Tapan Behl

Deepak Parashar

Ravi Rawat

Affiliations

Soon will be listed here.

Abstract

The Kirsten rat sarcoma viral oncogene homologue (KRAS) mutation is one of the most prevailing mutations in various tumors and is difficult to cure. Long-term proliferation in carcinogenesis is primarily initiated by oncogenic KRAS-downstream signaling. Recent research suggests that it also activates the autocrine effect and interplays the tumor microenvironment (TME). Here, we discuss the emerging research, including KRAS mutations to immune evasion in TME, which induce immunological modulation that promotes tumor development. This review gives an overview of the existing knowledge of the underlying connection between KRAS mutations and tumor immune modulation. It also addresses the mechanisms to reduce the effect of oncogenes on the immune system and recent advances in clinical trials for immunotherapy in KRAS-mutated cancers.

References

Le D, Uram J, Wang H, Bartlett B, Kemberling H, Eyring A . PD-1 Blockade in Tumors with Mismatch-Repair Deficiency. N Engl J Med. 2015; 372(26):2509-20. PMC: 4481136. DOI: 10.1056/NEJMoa1500596. View

Piulats J, Guerra E, Gil-Martin M, Roman-Canal B, Gatius S, Sanz-Pamplona R . Molecular approaches for classifying endometrial carcinoma. Gynecol Oncol. 2017; 145(1):200-207. DOI: 10.1016/j.ygyno.2016.12.015. View

Wood K, Hensing T, Malik R, Salgia R . Prognostic and Predictive Value in KRAS in Non-Small-Cell Lung Cancer: A Review. JAMA Oncol. 2016; 2(6):805-12. DOI: 10.1001/jamaoncol.2016.0405. View

Hanahan D, Weinberg R . The hallmarks of cancer. Cell. 2000; 100(1):57-70. DOI: 10.1016/s0092-8674(00)81683-9. View

Bellio H, Fumet J, Ghiringhelli F . Targeting BRAF and RAS in Colorectal Cancer. Cancers (Basel). 2021; 13(9). PMC: 8124706. DOI: 10.3390/cancers13092201. View

Sideris M, Emin E, Abdullah Z, Hanrahan J, Stefatou K, Sevas V . The Role of KRAS in Endometrial Cancer: A Mini-Review. Anticancer Res. 2019; 39(2):533-539. DOI: 10.21873/anticanres.13145. View

Timar J, Kashofer K . Molecular epidemiology and diagnostics of KRAS mutations in human cancer. Cancer Metastasis Rev. 2020; 39(4):1029-1038. PMC: 7680318. DOI: 10.1007/s10555-020-09915-5. View

Dearden S, Stevens J, Wu Y, Blowers D . Mutation incidence and coincidence in non small-cell lung cancer: meta-analyses by ethnicity and histology (mutMap). Ann Oncol. 2013; 24(9):2371-6. PMC: 3755331. DOI: 10.1093/annonc/mdt205. View

Pylayeva-Gupta Y, Grabocka E, Bar-Sagi D . RAS oncogenes: weaving a tumorigenic web. Nat Rev Cancer. 2011; 11(11):761-74. PMC: 3632399. DOI: 10.1038/nrc3106. View

10.

Ebi H, Corcoran R, Singh A, Chen Z, Song Y, Lifshits E . Receptor tyrosine kinases exert dominant control over PI3K signaling in human KRAS mutant colorectal cancers. J Clin Invest. 2011; 121(11):4311-21. PMC: 3204842. DOI: 10.1172/JCI57909. View

11.

Hashimoto S, Furukawa S, Hashimoto A, Tsutaho A, Fukao A, Sakamura Y . ARF6 and AMAP1 are major targets of and mutations to promote invasion, PD-L1 dynamics, and immune evasion of pancreatic cancer. Proc Natl Acad Sci U S A. 2019; 116(35):17450-17459. PMC: 6717289. DOI: 10.1073/pnas.1901765116. View

12.

Dong Z, Zhong W, Zhang X, Su J, Xie Z, Liu S . Potential Predictive Value of and Mutation Status for Response to PD-1 Blockade Immunotherapy in Lung Adenocarcinoma. Clin Cancer Res. 2017; 23(12):3012-3024. DOI: 10.1158/1078-0432.CCR-16-2554. View

13.

Sumimoto H, Takano A, Teramoto K, Daigo Y . RAS-Mitogen-Activated Protein Kinase Signal Is Required for Enhanced PD-L1 Expression in Human Lung Cancers. PLoS One. 2016; 11(11):e0166626. PMC: 5112979. DOI: 10.1371/journal.pone.0166626. View

14.

Eulenfeld R, Schaper F . A new mechanism for the regulation of Gab1 recruitment to the plasma membrane. J Cell Sci. 2008; 122(Pt 1):55-64. DOI: 10.1242/jcs.037226. View

15.

Schmid S, Gautschi O, Rothschild S, Mark M, Froesch P, Klingbiel D . Clinical Outcome of ALK-Positive Non-Small Cell Lung Cancer (NSCLC) Patients with De Novo EGFR or KRAS Co-Mutations Receiving Tyrosine Kinase Inhibitors (TKIs). J Thorac Oncol. 2016; 12(4):681-688. DOI: 10.1016/j.jtho.2016.12.003. View

16.

Vetter I, Wittinghofer A . The guanine nucleotide-binding switch in three dimensions. Science. 2001; 294(5545):1299-304. DOI: 10.1126/science.1062023. View

17.

Raj N, Klimstra D, Horvat N, Zhang L, Chou J, Capanu M . O6-Methylguanine DNA Methyltransferase Status Does Not Predict Response or Resistance to Alkylating Agents in Well-Differentiated Pancreatic Neuroendocrine Tumors. Pancreas. 2017; 46(6):758-763. PMC: 5509357. DOI: 10.1097/MPA.0000000000000842. View

18.

Glorieux C, Xia X, He Y, Hu Y, Cremer K, Robert A . Regulation of PD-L1 expression in K-ras-driven cancers through ROS-mediated FGFR1 signaling. Redox Biol. 2020; 38:101780. PMC: 7658718. DOI: 10.1016/j.redox.2020.101780. View

19.

Bogani G, Ricci M, Vitellaro M, Ditto A, Chiappa V, Raspagliesi F . Impact of gene-specific germline pathogenic variants on presentation of endometrial cancer in Lynch syndrome. Int J Gynecol Cancer. 2019; 29(4):705-710. DOI: 10.1136/ijgc-2019-000277. View

20.

Mazieres J, Drilon A, Lusque A, Mhanna L, Cortot A, Mezquita L . Immune checkpoint inhibitors for patients with advanced lung cancer and oncogenic driver alterations: results from the IMMUNOTARGET registry. Ann Oncol. 2019; 30(8):1321-1328. PMC: 7389252. DOI: 10.1093/annonc/mdz167. View