Tumor regression and resistance mechanisms upon CDK4 and RAF1 inactivation in KRAS/P53 mutant lung adenocarcinomas.
作者： Laura Esteban-Burgos , Haiyun Wang , Patricia Nieto , Jie Zheng , Carmen Blanco-Aparicio
关键词: Cancer research 、 Tumor progression 、 Lung cancer 、 PI3K/AKT/mTOR pathway 、 MAPK/ERK pathway 、 DNA methylation 、 Medicine 、 Cyclin-dependent kinase 、 Population 、 KRAS
摘要: KRAS mutant lung adenocarcinomas remain intractable for targeted therapies. Genetic interrogation of downstream effectors, including the MAPK pathway and interphase CDKs, identified CDK4 RAF1 as only targets whose genetic inactivation induces therapeutic responses without causing unacceptable toxicities. Concomitant ablation prevented tumor progression induced complete regression in 25% KRAS/p53-driven advanced tumors, yet a significant percentage those tumors that underwent partial retained population CDK4/RAF1-resistant cells. Characterization these cells revealed two independent resistance mechanisms implicating hypermethylation several suppressors increased PI3K activity. Importantly, can be pharmacologically controlled. These studies open door to new strategies treat cancer, resistant tumors.
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