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Overcoming KRAS-Mutant Lung Cancer
Jia Luo1,2, Jonathan Ostrem1,2, Bruna Pellini3
1Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, MA.
Abstract:
More than 50 years after the discovery of RAS family proteins, which harbor the most common activating mutations in cancer, the U.S. Food and Drug Administration approved the first direct allele-specific inhibitor of mutant KRAS in lung cancer. We highlight the history of discovering RAS and decades of studies targeting KRAS-driven lung cancer. A landmark article by Shokat and colleagues in 2013 elucidated allosteric inhibition of this undruggable target and paved the way for the first-in-class direct KRASG12C inhibitor. Although these drugs have impressive 36%-45% objective response rates with a median duration of response of 10 months, many tumors do not respond, and diverse mechanisms of resistance have already been observed; this includes new KRAS alterations, activation of alternate RTK pathway proteins, bypass pathways, and transcriptional remodeling. These resistance mechanisms can be profiled using tissue-based and plasma-based testing and help to inform clinical trial options for patients. We conclude with a discussion of research informing ongoing clinical trials to rationally test promising treatments to thwart or overcome resistance to KRASG12C inhibitors and target other KRAS-altered lung cancers.
Insights
The first KRAS G12C inhibitor offers new hope for lung cancer patients, but resistance mechanisms necessitate further research into overcoming treatment challenges and targeting other KRAS alterations.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- RAS family proteins are frequently mutated in cancer, driving tumor growth.
- Targeting KRAS mutations, particularly KRAS G12C, has been a long-standing challenge in lung cancer therapy.
- Recent advances led to the FDA approval of the first direct KRAS G12C inhibitor.
Purpose of the Study:
- To review the history of RAS protein discovery and KRAS-driven lung cancer research.
- To discuss the efficacy and limitations of the first KRAS G12C inhibitor.
- To explore resistance mechanisms and future therapeutic strategies for KRAS-altered lung cancers.
Main Methods:
- Literature review of RAS protein discovery and KRAS inhibitor development.
- Analysis of clinical trial data for KRAS G12C inhibitors.
- Discussion of molecular mechanisms of resistance and profiling techniques.
Main Results:
- The first direct KRAS G12C inhibitor shows objective response rates of 36%-45% with a 10-month median duration of response.
- Tumor non-response and acquired resistance are significant clinical challenges.
- Identified resistance mechanisms include new KRAS alterations, RTK pathway activation, bypass pathways, and transcriptional remodeling.
Conclusions:
- While the KRAS G12C inhibitor represents a breakthrough, overcoming resistance is crucial for improving patient outcomes.
- Profiling resistance mechanisms aids in selecting appropriate clinical trials.
- Future research should focus on combination therapies and targeting other KRAS alterations in lung cancer.
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