Tumor regression and resistance mechanisms upon CDK4 and RAF1 inactivation in KRAS/P53 mutant lung adenocarcinomas.

Esteban-Burgos, L.; Wang, H.; Nieto, P.; Zheng, J.; Blanco-Aparicio, C.; Varela, C.; Gómez-López, G.; Fernández-García, F.; Sanclemente, M.; Guerra, C.; Drosten, M.; Galán, J.; Caleiras, E.; Martínez-Torrecuadrada, J.; Fajas, L.; Peng, S.B.; Santamaría, D.; Musteanu, M.; Barbacid, M.

doi:10.1073/pnas.2002520117

Tumor regression and resistance mechanisms upon CDK4 and RAF1 inactivation in KRAS/P53 mutant lung adenocarcinomas.

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Serval ID

serval:BIB_05519E55AA11

Type

Article: article from journal or magazin.

Collection

Publications

Institution

UNIL/CHUV

Title

Tumor regression and resistance mechanisms upon CDK4 and RAF1 inactivation in KRAS/P53 mutant lung adenocarcinomas.

Journal

Proceedings of the National Academy of Sciences of the United States of America

Author(s)

Esteban-Burgos L., Wang H., Nieto P., Zheng J., Blanco-Aparicio C., Varela C., Gómez-López G., Fernández-García F., Sanclemente M., Guerra C., Drosten M., Galán J., Caleiras E., Martínez-Torrecuadrada J., Fajas L., Peng S.B., Santamaría D., Musteanu M., Barbacid M.

ISSN

1091-6490 (Electronic)

ISSN-L

0027-8424

Publication state

Published

Issued date

29/09/2020

Peer-reviewed

Oui

Volume

117

Number

Pages

24415-24426

Language

english

Notes

Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: ppublish

Abstract

KRAS mutant lung adenocarcinomas remain intractable for targeted therapies. Genetic interrogation of KRAS downstream effectors, including the MAPK pathway and the interphase CDKs, identified CDK4 and RAF1 as the only targets whose genetic inactivation induces therapeutic responses without causing unacceptable toxicities. Concomitant CDK4 inactivation and RAF1 ablation prevented tumor progression and induced complete regression in 25% of KRAS/p53-driven advanced lung tumors, yet a significant percentage of those tumors that underwent partial regression retained a population of CDK4/RAF1-resistant cells. Characterization of these cells revealed two independent resistance mechanisms implicating hypermethylation of several tumor suppressors and increased PI3K activity. Importantly, these CDK4/RAF1-resistant cells can be pharmacologically controlled. These studies open the door to new therapeutic strategies to treat KRAS mutant lung cancer, including resistant tumors.

Keywords

Adenocarcinoma of Lung/drug therapy, Adenocarcinoma of Lung/genetics, Adenocarcinoma of Lung/metabolism, Adenocarcinoma of Lung/pathology, Animals, Antineoplastic Agents/administration & dosage, Cell Line, Tumor, Cyclin-Dependent Kinase 4/genetics, Cyclin-Dependent Kinase 4/metabolism, Disease Progression, Drug Resistance, Neoplasm, Gene Silencing, Humans, Lung Neoplasms/drug therapy, Lung Neoplasms/genetics, Lung Neoplasms/metabolism, Lung Neoplasms/pathology, Mice, Mice, Inbred C57BL, Mutation, Proto-Oncogene Proteins c-raf/genetics, Proto-Oncogene Proteins c-raf/metabolism, Proto-Oncogene Proteins p21(ras)/genetics, Proto-Oncogene Proteins p21(ras)/metabolism, Tumor Suppressor Protein p53/genetics, Tumor Suppressor Protein p53/metabolism, CDK4/RAF1 inhibition, KRAS, Lung Cancer, Resistance Mechanisms, Tumor Regression

OAI-PMH

oai:serval.unil.ch:BIB_05519E55AA11

DOI

10.1073/pnas.2002520117

Pubmed

32913049

Web of science

000576672700024

Open Access

Yes

Create date

19/09/2020 13:23