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Updated: Jul 11, 2025
Author Spotlight: Advancements in Molecular Biomarker Testing for Non-Squamous Non-Small Cell Lung Cancer
Published on: September 8, 2023
The current landscape of using direct inhibitors to target KRASG12C-mutated NSCLC
Firas Batrash1, Mahmoud Kutmah1, Jun Zhang2,3
1School of Medicine, University of Missouri Kansas City, Kansas City, MO, 64108, USA.
Abstract:
Mutation in KRAS protooncogene represents one of the most common genetic alterations in NSCLC and has posed a great therapeutic challenge over the past ~ 40 years since its discovery. However, the pioneer work from Shokat's lab in 2013 has led to a recent wave of direct KRASG12C inhibitors that utilize the switch II pocket identified. Notably, two of the inhibitors have recently received US FDA approval for their use in the treatment of KRASG12C mutant NSCLC. Despite this success, there remains the challenge of combating the resistance that cell lines, xenografts, and patients have exhibited while treated with KRASG12C inhibitors. This review discusses the varying mechanisms of resistance that limit long-lasting effective treatment of those direct inhibitors and highlights several novel therapeutic approaches including a new class of KRASG12C (ON) inhibitors, combinational therapies across the same and different pathways, and combination with immunotherapy/chemotherapy as possible solutions to the pressing question of adaptive resistance.
Insights
KRAS G12C inhibitors offer new hope for non-small cell lung cancer (NSCLC) treatment. This review explores resistance mechanisms and novel strategies, including combination therapies, to overcome treatment challenges.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- KRAS protooncogene mutations are common in non-small cell lung cancer (NSCLC), presenting a significant therapeutic challenge for decades.
- Recent advancements have led to direct KRAS G12C inhibitors, with two FDA-approved treatments for KRAS G12C mutant NSCLC.
Purpose of the Study:
- To review mechanisms of resistance to KRAS G12C inhibitors in NSCLC.
- To highlight novel therapeutic strategies to overcome adaptive resistance.
Main Methods:
- Literature review of resistance mechanisms to KRAS G12C inhibitors.
- Analysis of emerging therapeutic approaches, including novel inhibitors and combination therapies.
Main Results:
- KRAS G12C inhibitors have shown success but face significant resistance challenges.
- Various resistance mechanisms limit the long-term efficacy of current treatments.
Conclusions:
- Overcoming resistance to KRAS G12C inhibitors is crucial for durable treatment responses in NSCLC.
- Novel therapeutic strategies, including new inhibitor classes and combination therapies, are essential to address adaptive resistance.
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