Abstract
Approximately 20% of lung adenocarcinomas harbor KRAS mutations, an oncogene that drives tumorigenesis and has the ability to alter the immune system and the tumor immune microenvironment. While KRAS was considered “undruggable” for decades, specific KRAS G12C covalent inhibitors have recently emerged, although their promising results are limited to a subset of patients. Several other drugs targeting KRAS activation and downstream signaling pathways are currently under investigation in early-phase clinical trials. In addition, KRAS mutations can co-exist with other mutations in significant genes in cancer (e.g., STK11 and KEAP1) which induces tumor heterogeneity and promotes different responses to therapies. This review describes the molecular characterization of KRAS mutant lung cancers from a biologic perspective to its clinical implications. We aim to summarize the tumor heterogeneity of KRAS mutant lung cancers and its immune-regulatory role, to report the efficacy achieved with current immunotherapies, and to overview the therapeutic approaches targeting KRAS mutations besides KRAS G12C inhibitors.
Highlights
After decades of research, the treatment efficacy of advanced lung cancer has remarkably improved, by incorporating novel therapeutic strategies including targeted therapies inhibiting specific genetically activated proteins, or immunotherapies such as immune-checkpoint inhibitors (ICI) [1]
Lung adenocarcinoma (LuAD) from smokers, the vast majority of KRAS mutations consist on guanine to thymine transversions, an effect that is associated with the tobacco carcinogens [5]
KRAS mutations in neversmokers are less frequent, and the most prevalent changes involve nucleotide transitions that replace the glycine in codon 12 by an aspartic acid (G12D) or a valine (G12V) [6, 7] (Figure 1)
Summary
The treatment efficacy of advanced lung cancer has remarkably improved, by incorporating novel therapeutic strategies including targeted therapies inhibiting specific genetically activated proteins, or immunotherapies such as immune-checkpoint inhibitors (ICI) [1]. In the case of sotorasib, this was based on the efficacy results of the phase I/II CodeBreak-100 trial (NCT03600883) that reported an objective response rate (ORR) of 32% and disease control rate (DCR) of 88% among lung cancer patients. Many other drugs targeting KRAS activation and other parallel and downstream pathways, as well as immunotherapeutic strategies, are currently under investigation in early-phase clinical trials [11].
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