Current therapy of KRAS-mutant lung cancer

Ghimessy, Aron and Radeczky, Peter and Laszlo, Viktoria and Hegedus, Balazs and Renyi-Vamos, Ferenc and Fillinger, Janos and Klepetko, Walter and Lang, Christian and Dome, Balazs and Megyesfalvi, Zsolt (2020) Current therapy of KRAS-mutant lung cancer. Cancer and Metastasis Reviews, 39 (4). pp. 1159-1177. ISSN 0167-7659

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Abstract

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, KRASrelated 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 KRASmutated LADC and provides an update on the most recent advances in KRAS-targeted anti-cancer strategies, with a focus on potential clinical implications.

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