A targeted genomic alteration analysis predicts survival of melanoma patients under BRAF inhibitors.

Baptiste Louveau,Julie Delyon,Coralie Reger De Moura,Marie-Pierre Podgorniak,Maxime Battistella,Jean-Paul Feugeas,Ichrak Chami,Lisa Golmard,Julie Caramel,Aurelie Sadoux,Samia Mourah,Stephane Dalle,Fanelie Jouenne,Oren Marco,Nicolas Dumaz,Celeste Lebbe

doi:10.18632/oncotarget.26707

Abstract

Several mechanisms have been described to elucidate the emergence of resistance to MAPK inhibitors in melanoma and there is a crucial need for biomarkers to identify patients who are likely to achieve a better and long-lasting response to BRAF inhibitors therapy. In this study, we developed a targeted approach combining both mRNA and DNA alterations analysis focusing on relevant gene alterations involved in acquired BRAF inhibitor resistance. We collected baseline tumor samples from 64 melanoma patients at BRAF inhibitor treatment initiation and showed that the presence, prior to treatment, of mRNA over-expression of genes’ subset was significantly associated with improved progression free survival and overall survival. The presence of DNA alterations was in favor of better overall survival. The genomic analysis of relapsed-matched tumor samples from 20 patients allowed us to uncover the largest landscape of resistance mechanisms reported to date as at least one resistance mechanism was identified for each patient studied. Alterations in RB1 have been most frequent and hence represent an important additional acquired resistance mechanism. Our targeted genomic analysis emerges as a relevant tool in clinical practice to identify those patients who are more likely to achieve durable response to targeted therapies and to exhaustively describe the spectrum of resistance mechanisms. Our approach can be adapted to new targeted therapies by including newly identified genetic alterations.

Highlights

In the last few years, therapies targeting the mitogen activated-protein kinase (MAPK) pathway have significantly extended progression free survival (PFS) and overall survival (OS) in patients with BRAFV600 mutated metastatic melanoma compared to chemotherapy [1,2,3].BRAFV600 mutations (BRAFV600mut) are detected in about 50% of lesions from metastatic melanoma patients and result in the constitutive activation of the MAPK pathway [4]
We developed a targeted genomic approach combining DNA and mRNA expression analysis which allowed the identification of acquired resistance mechanisms to BRAF inhibitors in all available relapse samples
Previous studies, which mainly focused on exome analysis, associated or not to mRNA analysis, have shown that over 25% relapsed BRAF inhibitor patients could not be attributed any known resistance mechanism

Summary

Introduction

In the last few years, therapies targeting the mitogen activated-protein kinase (MAPK) pathway have significantly extended progression free survival (PFS) and overall survival (OS) in patients with BRAFV600 mutated metastatic melanoma compared to chemotherapy [1,2,3].BRAFV600 mutations (BRAFV600mut) are detected in about 50% of lesions from metastatic melanoma patients and result in the constitutive activation of the MAPK pathway [4]. First used as a monotherapy, BRAF inhibitors, vemurafenib (Zelboraf®) and dabrafenib (Tafinlar®), have undergone multiple resistance mechanisms and their association with MEK inhibitors has become the standard of care [5,6,7] in order to reduce the occurrence of resistance. In this context, the identification of biomarkers enabling a better understanding of the mechanisms of MAPK inhibitor resistance constitutes a great challenge to stratify subsets of patients more likely to achieve long lasting responses and to predict clinical benefit of such targeted therapies. Activation of the PI3K/AKT pathway consecutive to PTEN loss and alterations of genes involved in cell cycle such as CDKN2A as well as the formation of eIF4F complex have been identified as resistance mechanisms [10,11,12,13,14]

Methods

Results

Conclusion