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Deficient Pms2, ERCC1, Ku86, CcOI in Field Defects During Progression to Colon Cancer
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Targeting KRAS G12C mutations in colorectal cancer

Ming-He Zhao1, Ai-Wen Wu1

  • 1Key Laboratory of Carcinogenesis and Translational Research, Ministry of Education; Unit III, Gastrointestinal Cancer Center, Peking University Cancer Hospital & Institute, Beijing, P. R. China.

Gastroenterology Report
|January 12, 2023
PubMed

Insights

KRAS G12C inhibitors offer new hope for RAS-mutated cancers, but resistance emerges quickly. This review explores combination therapies to overcome resistance mechanisms in colorectal cancer.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • The development of Kirsten rat sarcoma viral oncogene homologue G12C (KRAS G12C) inhibitors has transformed the treatment landscape for RAS-driven cancers, previously considered undruggable.
  • Despite initial therapeutic success, acquired resistance to KRAS G12C inhibitors is a significant clinical challenge, leading to short-lived tumor suppression.

Purpose of the Study:

  • To review current combination therapy strategies aimed at overcoming therapeutic resistance to KRAS G12C inhibitors in colorectal cancer.
  • To analyze the underlying mechanisms contributing to acquired resistance, including genetic alterations and pathway reactivation/stimulation.

Main Methods:

  • Comprehensive literature review of preclinical and clinical studies.
  • Analysis of mechanisms driving therapeutic resistance to KRAS G12C inhibitors.
  • Evaluation of combination therapy approaches to mitigate resistance.

Main Results:

  • Resistance to KRAS G12C inhibitors is multifactorial, involving acquired genetic alterations, reactivation of downstream signaling pathways, and compensatory upstream signaling.
  • Combination therapies targeting these resistance mechanisms show promise in preclinical models.
  • Understanding the interplay between resistance mechanisms is crucial for effective treatment strategies.

Conclusions:

  • Combination therapies are essential to overcome resistance and improve long-term outcomes for patients with KRAS G12C-mutated colorectal cancer.
  • Further research is needed to elucidate the complex resistance networks and optimize therapeutic combinations.
Keywords:
G12CKRAScolorectal neoplasmscombination therapydrug resistance

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