Exposing KRAS G12C: Not Your Usual Suspect in NSCLC
KRAS G12C Drives Oncogenesis and Supports Immune Evasion
KRAS Is an Intracellular Molecule That Regulates Normal Cellular Processes
Illustration. Role of KRAS in normal environment. KRAS acts as an intracellular switch, regulating pathways involved in normal cellular function including proliferation, apoptosis, differentiation, and survival.
KRAS G12C Drives Oncogenesis and Evades the Immune System
KRAS G12C is a single base missense mutation in exon 2 codon 12 where glycine is substituted with cysteine.2-4
This substitution blocks both the normal self-regulation of KRAS (intrinsic hydrolysis) and the external regulation provided by GTPase-activating (GAP) proteins. This substitution impacts the hydrolysis of guanosine triphosphate (GTP), leaving GTP bound longer to the protein and longer in its active state.1,3,4
In this constantly active state, KRAS G12C drives downstream signaling pathways rather than acting as a controlled switch. However, some cycling between GTP and guanosine diphosphate (GDP) does continue to occur.1,3,4
Illustration: Mutated KRAS G12C drives oncogenesis and supports immune evasion. It is constitutively activated leading to overstimulation of downstream signaling pathways leading to tumor formation. Additionally, KRAS G12C also impacts the tumor microenvironment by evading the immune system, further supporting in tumor survival.
Altogether, the constitutively activated KRAS G12C not only leads to tumor formation but also supports immune evasion, creating a favorable environment for tumor survival.1,3,4,5
Once Considered "Undruggable", KRAS G12C Currently Has Approved (in 2L / Later Settings) and Investigational Targeted Inhibitors1,3,4,8
What does having a tumor with KRAS G12C protein mean for your patients?
KRAS G12C exerts two effects: oncogenesis and immune evasion, rendering it more favorable to trick the immune system.
Knowing that your patients with KRAS G12C–mutant NSCLC have tumor cells with uncontrolled oncogenic signaling pathways constitutively switched on and a suppressive TME focused on immune evasion, how might these factors impact your considerations for them?
Discover what treatment strategies could be used to address the effects exerted by the KRAS G12C protein by continuing to the next section.
AKT = protein kinase B; ATP = adenosine triphosphate; CD = cluster of differentiation; GAP = GTPase-activating protein; GDP = guanosine diphosphate; GTP = guanosine triphosphate; KRAS = Kirsten rat sarcoma; MAPK = mitogen-activated kinase; MDSC = myeloid-derived suppressor cell; MEK = mitogen-activated protein kinase; MHC = major histocompatibility complex; mTOR = mammalian target of rapamycin; NET = neutrophil extracellular trap; NK = natural killer; NSCLC = non-small cell lung cancer; PD-L1 = programmed death-ligand 1; PI3K = phosphatidylinositol 3-kinase; RAF = rapidly accelerated fibrosarcoma; RAL = Ras-like protein; S-IIP = switch-II pocket; TME = tumor microenvironment; TP53 = tumor protein p53; Treg = regulatory T cell.
References
- Singhal A, et al. Targeting KRAS in cancer. Nat Med. 2024;30(4):969-983.
- Chevallier M, et al. Oncogenic driver mutations in non-small cell lung cancer: past, present and future. World J Clin Oncol. 2021;12(4):217-237.
- Ferreira A, et al. Crucial role of oncogenic KRAS mutations in apoptosis and autophagy regulation: therapeutic implications. Cells. 2022;11(14):2183.
- Lim TKH, et al. KRAS G12C in advanced NSCLC: prevalence, co-mutations, and testing. Lung Cancer. 2023;184:107293.
- Huang L, et al. KRAS mutation: from undruggable to druggable in cancer. Signal Transduct Target Ther. 2021;6(1):386.
- Xu M, et al. Unveiling the role of KRAS in tumor immune microenvironment. Biomed & Pharmacother. 2024;171:116058.
- Alsaed B, et al. Shaping the battlefield: EGFR and KRAS tumor mutations' role on the immune microenvironment and immunotherapy responses in lung cancer. Cancer Metastasis Rev. 2025;44(3):56.
- Ostrem JM, et al. K-Ras(G12C) inhibitors allosterically control GTP affinity and effector interactions. Nature. 2013;503(7477):548-51.
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