Tumor regression and resistance mechanisms upon CDK4 and RAF1 inactivation in KRAS/P53 mutant lung adenocarcinomas
2020; National Academy of Sciences; Volume: 117; Issue: 39 Linguagem: Inglês
10.1073/pnas.2002520117
ISSN1091-6490
AutoresLaura Esteban-Burgos, Haiyun Wang, Patricia Nieto, Jie Zheng, Carmen Blanco‐Aparicio, Carmen Varela, Gonzalo Gómez‐López, Fernando Fernández-García, Manuel Sanclemente, Carmen Guerra, Matthias Drosten, Javier Galán, Eduardo Caleiras, Jorge L. Martı́nez-Torrecuadrada, Lluís Fajas, Sheng-Bin Peng, David Santamarı́a, Mónica Musteanu, Mariano Barbacid,
Tópico(s)Ubiquitin and proteasome pathways
ResumoSignificance So far, no targeted therapy has been approved for KRAS mutant tumors. We report that combined genetic inactivation of CDK4 and RAF1 in advanced KRAS/p53 mutant lung tumors leads to effective tumor regression without inducing significant toxicities. In spite of this therapeutic response, CDK4/RAF1-resistant cells appeared. We have identified and pharmacologically validated two independent resistance mechanisms involving hypermethylation of tumor-suppressor genes and activation of the PI3K pathway.
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