Implications of KRAS mutations in acquired resistance to treatment in NSCLC.

Marzia Del Re,Stefano Fogli,Stefania Crucitta,Eleonora Rofi,Giuliana Restante,Elena Arrigoni,Massimo Di Maio,Romano Danesi,Iacopo Petrini

doi:10.18632/oncotarget.23553

Marzia Del Re, Stefano Fogli + Show 7 more

Open Access

https://doi.org/10.18632/oncotarget.23553

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Journal: Oncotarget	Publication Date: Dec 21, 2017
Citations: 42	License type: cc-by

Affiliation: University of Pisa, University of Turin

Abstract

RationaleKRAS is the most common and, simultaneously, the most ambiguous oncogene implicated in human cancer. Despite KRAS mutations were identified in Non Small Cell Lung Cancers (NSCLCs) more than 20 years ago, selective and specific inhibitors aimed at directly abrogating KRAS activity are not yet available. Nevertheless, many therapeutic approaches have been developed potentially useful to treat NSCLC patients mutated for KRAS and refractory to both standard chemotherapy and targeted therapies.The focus of this review will be to provide an overview of the network related to the intricate molecular KRAS pathways, stressing on preclinical and clinical studies that investigate the predictive value of KRAS mutations in NSCLC patients.Materials and MethodsA bibliographic search of the Medline database was conducted for articles published in English, with the keywords KRAS, KRAS mutations in non-small cell lung cancer, KRAS and tumorigenesis, KRAS and TKIs, KRAS and chemotherapy, KRAS and monoclonal antibody, KRAS and immunotherapy, KRAS and drugs, KRAS and drug resistance.

Highlights

Lung cancer is the leading cause of cancerrelated death worldwide, despite a reduced incidence in western countries and a remarkable improvement in its therapeutic approach
The focus of this review will be to provide an overview of the network related to the intricate molecular KRAS pathways, stressing on preclinical and clinical studies that investigate the predictive value of KRAS mutations in Non Small Cell Lung Cancers (NSCLCs) patients
This review focuses on the molecular pathways of KRAS in order to point out possible targets for an anti-KRAS approach reporting success and failures of compounds developed to date

Summary

Introduction

Lung cancer is the leading cause of cancerrelated death worldwide, despite a reduced incidence in western countries and a remarkable improvement in its therapeutic approach. Non Small Cell Lung Cancer (NSCLC) is the most common diagnosis and the adenocarcinoma is the predominant subtype [1]. Several driver mutations have been described, in the recent years, in lung adenocarcinomas including those affecting KRAS (15-25%) and EGFR (10-35%). Rearrangements involving ALK, ROS1 or RET locus have been identified [2]. The majority of these alterations are targetable by the EGFR tyrosine kinase inhibitors (TKIs) (i.e. gefitinib, erlotinib, afatinib in EGFR-mutant; crizotinib, ceritinib, brigatinib, and alectinib in ALK rearranged tumors) [3,4,5,6,7,8]

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