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Targeting KRAS for cancer therapy

Jianlong Jia1,2, Ruonan Liu3,4, Tonia A Adamide5

  • 1Institute of Lung Health and Immunity (LHI), Comprehensive Pneumology Center (CPC), Helmholtz Munich, Member of the German Center for Lung Research (DZL), Munich, Germany.

British Journal of Pharmacology
|July 1, 2026
PubMed

Insights

Targeting KRAS-mutant cancers shows promise. New strategies for KRAS G12C and other mutations, including resistance mechanisms and novel dosing frameworks, aim to improve patient outcomes.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • KRAS proto-oncogene GTPase (KRAS)-mutant cancers are a significant therapeutic challenge.
  • Recent advancements have led to targeted therapies for KRAS-mutant cancers, particularly KRAS G12C.
  • Understanding KRAS alterations, resistance mechanisms, and adaptive pathways is crucial for improving treatment efficacy.

Purpose of the Study:

  • To review the biology and epidemiology of KRAS alterations.
  • To summarize clinical evidence for KRAS G12C inhibitors and explore strategies for non-KRAS G12C mutations.
  • To propose a novel framework for optimizing therapeutic interventions and patient survival.

Main Methods:

  • Literature review of KRAS biology, epidemiology, and clinical trial data.
  • Analysis of resistance mechanisms, including secondary mutations and adaptive circuits.
  • Development of a 'three-clock, two-window' framework for dosing optimization.
  • Proposal of a closed-loop system integrating biomarker dynamics (ctDNA, pERK) and imaging for treatment monitoring.

Main Results:

  • KRAS G12C inhibitors like sotorasib and adagrasib demonstrate clinical efficacy.
  • Non-KRAS G12C strategies, including RAS (ON)- and KRAS G12D-selective approaches, show early promise.
  • Identification of resistance mechanisms and adaptive cellular reprogramming.
  • A proposed framework and closed-loop system for enhanced therapeutic control.

Conclusions:

  • Targeted KRAS inhibition has revolutionized cancer therapy.
  • Addressing resistance and exploring non-G12C mutations are key future directions.
  • Optimized dosing strategies and integrated biomarker monitoring can improve durable inhibition and survival in KRAS-mutant cancers.
Keywords:
KRASKRAS inhibitorsKRAS mutationscombination therapytherapeutic resistance

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