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Published on: July 21, 2018
On target: Rational approaches to KRAS inhibition for treatment of non-small cell lung carcinoma
Colin R Lindsay1, Marina C Garassino2, Ernest Nadal3
1Division of Cancer Sciences, University of Manchester, Manchester, UK; Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, UK; Cancer Research UK Lung Cancer Centre of Excellence, Manchester and London, UK.
Abstract:
Non-small cell lung carcinoma (NSCLC) is a leading cause of cancer death. Approximately one-third of patients with NSCLC have a KRAS mutation. KRASG12C, the most common mutation, is found in ~13% of patients. While KRAS was long considered 'undruggable', several novel direct KRASG12C inhibitors have shown encouraging signs of efficacy in phase I/II trials and one of these (sotorasib) has recently been approved by the US Food and Drug Administration. This review examines the role of KRAS mutations in NSCLC and the challenges in targeting KRAS. Based on specific KRAS biology, it reports exciting progress, exploring the use of novel direct KRAS inhibitors as monotherapy or in combination with other targeted therapies, chemotherapy, and immunotherapy.
Insights
Novel KRAS G12C inhibitors show promise for non-small cell lung cancer (NSCLC). This review explores targeting KRAS mutations, offering new therapeutic strategies for NSCLC patients.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Non-small cell lung carcinoma (NSCLC) is a major cause of cancer mortality.
- KRAS mutations are prevalent in NSCLC, with KRAS G12C being the most common (~13%).
- Historically, KRAS was considered undruggable, limiting treatment options.
Purpose of the Study:
- To review the role of KRAS mutations in NSCLC pathogenesis.
- To discuss the challenges and advancements in targeting KRAS mutations.
- To explore emerging therapeutic strategies involving KRAS G12C inhibitors.
Main Methods:
- Literature review of preclinical and clinical studies on KRAS mutations in NSCLC.
- Analysis of data from Phase I/II trials of KRAS G12C inhibitors.
- Examination of KRAS biology and drug development landscape.
Main Results:
- Several novel direct KRAS G12C inhibitors demonstrate efficacy in early-phase trials.
- Sotorasib, a KRAS G12C inhibitor, has received FDA approval.
- Combinatorial approaches with KRAS inhibitors are under investigation.
Conclusions:
- Targeting KRAS G12C represents a significant breakthrough in NSCLC treatment.
- KRAS inhibitors offer new hope as monotherapy or in combination regimens.
- Further research is crucial to optimize treatment strategies for KRAS-mutated NSCLC.
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