Identifying the spectrum of genetic alterations that cooperate with critical oncogenes to promote transformation provides a foundation for understanding the diversity of clinical phenotypes observed in human cancers. Here, we performed integrated analyses to identify genomic alterations that co-occur with oncogenic BRAF in melanoma and abrogate cellular dependence upon this oncogene. We identified concurrent mutational inactivation of the PTEN and RB1 tumor suppressors as a mechanism for loss of BRAF/MEK dependence in melanomas harboring V600E BRAF mutations. RB1 alterations were mutually exclusive with loss of p16 INK4A, suggesting that whereas p16 INK4A and RB1 may have overlapping roles in preventing tumor formation, tumors with loss of RB1 exhibit diminished dependence upon BRAF signaling for cell proliferation. These findings provide a genetic basis for the heterogeneity of clinical outcomes in patients treated with targeted inhibitors of the mitogen-activated protein kinase pathway. Our results also suggest a need for comprehensive screening for RB1 and PTEN inactivation in patients treated with RAF and MEK-selective inhibitors to determine whether these alterations are associated with diminished clinical benefit in patients whose cancers harbor mutant BRAF.
|Number of pages
|Published - Jan 26 2012
Bibliographical noteFunding Information:
We thank Drs Meenhard Herlyn and Kate Nathanson (University of Pennsylvania) and Dr Øystein Fodstad (Department of Tumor Biology of The Norwegian Radium Hospital, Norway) for kindly providing cell lines. This study was supported by grants from the National Institutes of Health (DBS), the Kimmel Foundation (DBS), Golfers-Against-Cancer (DBS), the Melanoma Research Alliance (DBS) and STARR Foundation (DBS). BST is the David H Koch Fellow in cancer genomics.
David Solit has received honoraria and research funding from AstraZeneca, and had an advisory role with Roche. Gideon Bollag is an employee of Plexxikon Inc.
- BRAF inhibitor
- MEK inhibitor
ASJC Scopus subject areas
- Molecular Biology
- Cancer Research