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ABSTRACT

KRAS mutations are responsible for a quarter of all lung adenocarcinomas. However, the molecular mechanisms linking these mutations and their frequent secondary dosage amplification to tumor formation are still not fully understood. While ample evidence supports a crucial role for the MAPK pathway in tumor development, the primary effectors targeted by this pathway remain largely unexplored. Here we identify the transcriptional repressor Capicua (CIC) as a key target inactivated by KRAS/MAPK signaling in lung adenocarcinoma. We show that genetic loss of CIC recapitulates the phenotypic consequences of amplified KRAS signaling. Genetic disruption of CIC suppressed the requirement for Kras allelic imbalances and accelerated the transformation of bronchiolar Club cells. We also demonstrate that restoring CIC repressor activity impaired proliferation of CIC-deficient tumor cells and reverted resistance to MAPK pathway inhibitors. These results highlight the key role of CIC during lung tumor formation and suggest that selective pressure for effective CIC inactivation favors secondary amplification of KRAS/MAPK signaling in tumor cells. The inactivation of the repressor Capicua (CIC) promotes the development of lung cancer in Kras/Trp53 mutant mice by transforming bronchiolar Club cells. Loss of CIC in lung cancer cells causes resistance to MAPK pathway inhibition while exposing new drug vulnerabilities. Absence of CIC abrogates the requirement for Kras oncogene amplifications in Kras/Trp53 mutant mice during tumor development. CIC deficiency promotes transformation of bronchiolar Club cells. Silencing of CIC target genes ETV4 and ETV5 restores the sensitivity to the MEK inhibitor trametinib in Cic-deficient tumor cells. Lung tumor cells lacking Cic display increased sensitivity to PFK15 and Tx-1123. Absence of CIC abrogates the requirement for Kras oncogene amplifications in Kras/Trp53 mutant mice during tumor development. CIC deficiency promotes transformation of bronchiolar Club cells. Silencing of CIC target genes ETV4 and ETV5 restores the sensitivity to the MEK inhibitor trametinib in Cic-deficient tumor cells. Lung tumor cells lacking Cic display increased sensitivity to PFK15 and Tx-1123. The inactivation of the repressor Capicua (CIC) promotes the development of lung cancer in Kras/Trp53 mutant mice by transforming bronchiolar club cells. Loss of CIC in lung cancer cells causes resistance to MAPK pathway inhibition while exposing new drug vulnerabilities.

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