Current therapy of KRAS-mutant lung cancer

KRAS mutations are the most frequent gain-of-function alterations in patients with lung adenocarcinoma (LADC) in the Western world. Although they have been identified decades ago, prior efforts to target KRAS signaling with single-agent therapeutic approaches such as farnesyl transferase inhibitors,...

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Published in:Cancer and metastasis reviews 2020-12, Vol.39 (4), p.1159-1177
Main Authors: Ghimessy, Aron, Radeczky, Peter, Laszlo, Viktoria, Hegedus, Balazs, Renyi-Vamos, Ferenc, Fillinger, Janos, Klepetko, Walter, Lang, Christian, Dome, Balazs, Megyesfalvi, Zsolt
Format: Article
Language:English
Subjects:
Adenocarcinoma
Analysis
Biomedical and Life Sciences
Biomedicine
Cancer Research
Development and progression
Genetic analysis
Health aspects
K-Ras protein
Lethality
Lung cancer
Lung cancer, Non-small cell
Mutation
Non-small cell lung carcinoma
Oncology
Patients
Pemetrexed
Small cell lung carcinoma
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Summary:KRAS mutations are the most frequent gain-of-function alterations in patients with lung adenocarcinoma (LADC) in the Western world. Although they have been identified decades ago, prior efforts to target KRAS signaling with single-agent therapeutic approaches such as farnesyl transferase inhibitors, prenylation inhibition, impairment of KRAS downstream signaling, and synthetic lethality screens have been unsuccessful. Moreover, the role of KRAS oncogene in LADC is still not fully understood, and its prognostic and predictive impact with regards to the standard of care therapy remains controversial. Of note, KRAS-related studies that included general non-small cell lung cancer (NSCLC) population instead of LADC patients should be very carefully evaluated. Recently, however, comprehensive genomic profiling and wide-spectrum analysis of other co-occurring genetic alterations have identified unique therapeutic vulnerabilities. Novel targeted agents such as the covalent KRAS G12C inhibitors or the recently proposed combinatory approaches are some examples which may allow a tailored treatment for LADC patients harboring KRAS mutations. This review summarizes the current knowledge about the therapeutic approaches of KRAS-mutated LADC and provides an update on the most recent advances in KRAS-targeted anti-cancer strategies, with a focus on potential clinical implications.
ISSN:0167-7659
1573-7233
DOI:10.1007/s10555-020-09903-9