KRAS

  • Kirsten rat sarcoma viral oncogene homologue (KRAS)
  • Gene location: chromosome 12 (12p11)

RAS Protein Family

  • RAS proteins (KRAS, NRAS, HRAS) are small GTPases that regulate essential cell signaling pathways, including MAPK, PI3K/mTOR, and RAL/NF-κB.1
  • They play a central role in controlling cell growth, differentiation, and survival.1
  • Mutations in RAS genes are among the most common oncogenic alterations, found in approximately 19% of all human cancers.2
  • These mutations are associated with poor prognosis and resistance to standard therapies, making RAS a major focus of ongoing cancer research.3

Biology

  • KRAS functions as a molecular switch, alternating between inactive (GDP-bound) and active (GTP-bound) states to control downstream signaling.1
  • Activation of KRAS is initiated by cell surface receptor tyrosine kinases (eg, EGFR, HER2, HER3, FGFR), which stimulate guanine nucleotide exchange factors (GEFs) like SOS1/2 to promote GDP-GTP exchange.1 
  • Once activated, KRAS dimerizes and initiates signaling cascades that regulate critical cellular processes.1
  • GTPase-activating proteins (GAPs) negatively regulate KRAS by converting KRAS-GTP back to KRAS-GDP.1
  • Activating mutations (most often at codons 12, 13, and 61) impair GTP hydrolysis, resulting in constitutive activation and persistent signaling—independent of growth factors. These mutations lead to uncontrolled proliferation, survival, and metastasis in cancer cells.4,5
  • Mutation-specific differences affect therapeutic targeting6:
    • KRAS G12C retains some GTPase activity and can be targeted with covalent inhibitors.
    • KRAS G12D and G12V lack sufficient GTPase activity, making them more challenging to target using the same approaches.

Epidemiology and Etiology

  • KRAS is the most commonly mutated RAS isoform in human cancers, especially in gastrointestinal (GI) malignancies7-9:
    • Colorectal cancer (CRC): KRAS mutations in 40% to 50% of cases
    • Pancreatic ductal adenocarcinoma (PDAC): Present in approximately 90% of cases.
    • Biliary tract cancer (BTC): Found in approximately 15% to 20% of cases.
  • Most prevalent KRAS variants by cancer type:
    • CRC: G12D, G12V, G13D
    • PDAC: G12D, G12V, G12R
    • BTC: G12D
  • KRAS G12C mutations are rare in GI cancers:
    • Approximately 3.6% in CRC
    • Approximately 1.5% in PDAC
    • Approximately 1% in BTC
  • Prognostic implications vary:
    • KRAS G12C is associated with worse outcomes in CRC.
    • KRAS G12R may indicate a more favorable prognosis.
    • KRAS mutations are linked to resistance to anti-EGFR therapies, diminishing the effectiveness of targeted treatments in CRC and other GI cancers.
    • Overall, KRAS mutations are associated with aggressive disease, poor prognosis, and limited treatment options, emphasizing the urgent need for effective targeted therapies.

Testing

When to Test10

  • All patients with metastatic CRC(mCRC) should have tumors genotyped for RAS (KRAS and NRAS) and BRAF mutations individually or as part of a next-generation sequencing (NGS) panel (preferred) at the time of diagnosis.
  • Patients with any known KRAS mutation (exons 2, 3, and4) or NRAS mutation (exons 2, 3, and 4) should not be treated with either cetuximab or panitumumab, unless given as part of a regimen targeting a KRAS G12C mutation.

Available Testing Methods10

  • Testing for KRAS, NRAS, and BRAF mutations should be conducted in Clinical Laboratory Improvement Amendments–certified laboratories qualified for high-complexity molecular testing.
  • No specific testing method is required; both NGS-based sequencing and in situ hybridization techniques are acceptable for detecting RAS and BRAF mutations. Immunohistochemistry may also be used to identify the BRAF V600E mutation.
  • Testing can be performed on either primary tumor tissue or metastatic lesions, as literature has shown that the KRAS, NRAS, and BRAF mutations are similar in both specimen types. 

Testing Guideline Recommendations10

  • All patients with mCRC should undergo testing for KRAS, NRAS and BRAF mutations, HER2 amplifications, and microsatellite instability/mismatch repair status; testing may be performed individually or via NGS (preferred).

Targeted Therapies

Approved Agents11,12

  • Two oral targeted therapies have received approval from FDA for the treatment of KRAS G12C–mutated locally advanced or metastatic CRC.
  • On June 21, 2024, the FDA granted accelerated approval to adagrasib (Krazati; Mirati Therapeutics, Inc) in combination with cetuximab for adults with KRAS G12C–mutated locally advanced or metastatic CRC, as confirmed by an FDA-approved test. Eligible patients must have received prior treatment with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy. This approval was supported by results from the KRYSTAL-1 trial (NCT03785249).
  • On January 16, 2025, the FDA approved sotorasib (Lumakras; Amgen Inc) in combination with panitumumab (Vectibix; Amgen Inc) for adults with KRAS G12C–mutated mCRC, as confirmed by an FDA-approved test, following prior fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy. Approval was based on findings from the CodeBreaK 300 study (NCT05198934).
  • In KRAS G12C–mutant CRC, EGFR activation has been recognized as a key mechanism of resistance to KRAS G12C inhibition. As a result, both KRAS G12C–targeted therapies have been approved in combination with EGFR inhibitors to enhance treatment efficacy.

Adagrasib13

  • FDA approved indication:
    • In combination with cetuximab, for the treatment of adult patients with KRAS G12C–mutated locally advanced or metastatic CRC, as determined by an FDA-approved test, who have received prior treatment with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy
    • This indication is approved under accelerated approval based on objective response rate and duration of response. Continued approval for these indications may be contingent on verification and description of a clinical benefit in confirmatory trials.
  • Mechanism of action:
    • Adagrasib is an irreversible inhibitor of KRAS G12C that covalently binds to the mutant cysteine in KRAS G12C and locks the mutant KRAS protein in its inactive state, preventing downstream signaling without affecting wild-type KRAS protein.
    • Adagrasib inhibited tumor cell growth and viability in cells harboring KRAS G12C mutations and resulted in tumor regression in KRAS G12C–mutated tumor xenograft models with minimal off-target activity.
    • Adagrasib in combination with cetuximab had increased antitumor activity in some cell line–derived and patient-derived KRAS G12C–mutant CRC tumor xenograft models compared withadagrasib or cetuximab alone.
    • Cetuximab is an EGFR inhibitor.
  • Drug information:
  • Patient resources:

Sotorasib14

  • FDA-approved indication:
    • In combination with panitumumab, for the treatment of adult patients with KRAS G12C–mutated mCRC, as determined by an FDA approved-test, who have received prior fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapy
  • Mechanism of action:
    • Sotorasib is an inhibitor of KRAS G12C, a tumor-restricted, mutant-oncogenic form of the RAS GTPase KRAS.
    • Sotorasib forms an irreversible, covalent bond with the unique cysteine of KRAS G12C, locking the protein in an inactive state that prevents downstream signaling without affecting wild-type KRAS. Sotorasib blocked KRAS signaling, inhibited cell growth, and promoted apoptosis only in KRAS G12C tumor cell lines.
    • Sotorasib inhibited KRAS G12C in vitro and in vivo with minimal detectable off-target activity. In mouse tumor xenograft models, sotorasib treatment led to tumor regressions and prolonged survival and was associated with antitumor immunity in KRAS G12C models.
    • Panitumumab is an EGFR inhibitor.
  • Drug information:
  • Patient resources:

References

  1. Abidoye O, Hoyek C, Bekaii-Saab T. Targeting RAS in gastrointestinal malignancies. Clin Adv Hematol Oncol. 2025;23(2):111-122.
  2. Prior IA, Hood FE, Hartley JL. The frequency of RAS mutations in cancer. Cancer Res. 2020;80(14):2969-2974.doi:10.1158/0008-5472.CAN-19-3682
  3. Singhal A, Li BT, O’Reilly EM. Targeting KRAS in cancer. Nat Med. 2024;30(4):969-983. doi:10.1038/s41591-024-02903-0
  4. Simanshu DK, Nissley DV, McCormick F. RAS proteins and their regulators in human disease. Cell. 2017;170(1):17-33.doi:10.1016/j.cell.2017.06.009
  5. Cook JH, Melloni GEM, Gulhan DC, Park PJ, Haigis KM. The origins and genetic interactions of KRAS mutations are allele- and tissue-specific. Nat Commun. 2021;12(1):1808. doi:10.1038/s41467-021-22125-z
  6. Hunter JC, Manandhar A, Carrasco MA, Gurbani D, Gondi S, Westover KD. Biochemical and structural analysis of common cancer-associated KRAS mutations. Mol Cancer Res. 2015;13(9):1325-1335.doi:10.1158/1541-7786.MCR-15-0203
  7. Cancer Genome Atlas Network. Comprehensive molecular characterization of human colon and rectal cancer. Nature. 2012;487(7407):330-337.doi:10.1038/nature11252
  8. Bailey P, Chang DK, Nones K, et al; Australian Pancreatic Cancer Genome Initiative. Genomic analyses identify molecular subtypes of pancreatic cancer. Nature. 2016;531(7592):47-52.doi:10.1038/nature16965
  9. Yaeger R, Chatila WK, Lipsyc MD, et al. Clinical sequencing defines the genomic landscape of metastatic colorectal cancer. Cancer Cell. 2018;33(1):125-136.e3.doi:10.1016/j.ccell.2017.12.004
  10. NCCN Clinical Practice Guidelines in Oncology. Colon cancer, version 3.2025. Accessed May 9, 2025. https://www.nccn.org/professionals/physician_gls/pdf/colon.pdf 
  11. FDA grants accelerated approval to adagrasib with cetuximab for KRAS G12C-mutated colorectal cancer. FDA. June 21, 2024. Accessed May 9, 2025.https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-adagrasib-cetuximab-kras-g12c-mutated-colorectal-cancer 
  12. FDA approves sotorasib with panitumumab for KRASG12C-mutated colorectal cancer. FDA. January 16, 2025. Accessed May 9, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-sotorasib-panitumumab-kras-g12c-mutated-colorectal-cancer 
  13. Krazati. Prescribing information. Mirati Therapeutics; 2024. Accessed May 9, 2025. https://packageinserts.bms.com/pi/pi_krazati.pdf 
  14. Lumakras. Prescribing information. Amgen Inc;2023. Accessed May 9, 2025. https://www.pi.amgen.com/-/media/Project/Amgen/Repository/pi-amgen-com/Lumakras/lumakras_pi_hcp_english.pdf