Role of the repressor Capicua in KRAS-driven lung tumor development.
Irene Ballesteros González
Centro de Investigación del Cáncer (CSIC, USAL, FICUS)
Mutations in KRAS are found in approximately 25% of lung adenocarcinomas. Although the recent development of KRAS inhibitors has offered new hope for patients with these tumors, most eventually develop resistance to these therapies. This underscores the need for a deeper understanding of KRAS signaling to inform combination strategies that could delay or prevent the rapid emergence of resistance.
We have identified the transcriptional repressor Capicua (CIC) as a central effector of KRAS/MAPK signaling in lung adenocarcinoma. We demonstrate that loss of CIC function recapitulates the key phenotypic consequences of oncogenic KRAS activation, suppresses the dependency on KRAS allelic imbalance, and accelerates the transformation of bronchiolar Club cells. As loss of CIC also promotes resistance to KRAS/MAPK pathway inhibition, we explore different strategies to target resistant tumor cells including restoration of CIC activity or identification of CIC target genes mediating resistance.
Together, these findings establish CIC as a critical regulator of lung tumorigenesis and suggest that selective pressure to abolish CIC function promotes the amplification of KRAS/MAPK signaling during tumor progression.