Work

Dasatinib induces DNA damage and activates DNA repair pathways leading to senescence in non-small cell lung cancer cell lines with kinase-inactivating BRAF mutations

Year: 2015

Type: article

Abstract: // Shaohua Peng 1 , Banibrata Sen 1, 2, * , Tuhina Mazumdar 1 , Lauren A. Byers 1, 3 , Lixia Diao 4 , Jing Wang 3, 4 , Pan Tong 4 , Uma Giri 1 , John V. Heymach 1, 3 , Humam N. Kadara 5 , Faye M. Johnson 1, 3 1 Department of Thoracic/Head & Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA 2 AstraZeneca Pharmaceuticals, London, UK 3 The University of Texas Graduate School of Biomedical Sciences, Houston, Texas, USA 4 Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA 5 Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA * Dr. Banibrata Sen was employed at The University of Texas MD Anderson Cancer Center at the time this research was performed Correspondence to: Faye M. Johnson, e-mail: [email protected] Keywords: lung cancer, BRAF, TAZ, DNA damage, kinase inhibition Received: June 03, 2015 Accepted: November 14, 2015 Published: November 23, 2015 ABSTRACT Improved therapies are greatly needed for non-small cell lung cancer (NSCLC) that does not harbor targetable kinase mutations or translocations. We previously demonstrated that NSCLC cells that harbor kinase-inactivating BRAF mutations ( KI BRAF ) undergo senescence when treated with the multitargeted kinase inhibitor dasatinib. Similarly, treatment with dasatinib resulted in a profound and durable response in a patient with KI BRAF NSCLC. However, no canonical pathways explain dasatinib-induced senescence in KI BRAF NSCLC. To investigate the underlying mechanism, we used 2 approaches: gene expression and reverse phase protein arrays. Both approaches showed that DNA repair pathways were differentially modulated between KI BRAF NSCLC cells and those with wild-type (WT) BRAF . Consistent with these findings, dasatinib induced DNA damage and activated DNA repair pathways leading to senescence only in the KI BRAF cells. Moreover, dasatinib-induced senescence was dependent on Chk1 and p21, proteins known to mediate DNA damage-induced senescence. Dasatinib also led to a marked decrease in TAZ but not YAP protein levels. Overexpression of TAZ inhibited dasatinib-induced senescence. To investigate other vulnerabilities in KI BRAF NSCLC cells, we compared the sensitivity of these cells with that of WT BRAF NSCLC cells to 79 drugs and identified a pattern of sensitivity to EGFR and MEK inhibitors in the KI BRAF cells. Clinically approved EGFR and MEK inhibitors, which are better tolerated than dasatinib, could be used to treat KI BRAF NSCLC. Our novel finding that dasatinib induced DNA damage and subsequently activated DNA repair pathways leading to senescence in KI BRAF NSCLC cells represents a unique vulnerability with potential clinical applications.

Source: Oncotarget

DOI: 10.18632/oncotarget.6376