BCL2A1 is a lineage-specific antiapoptotic melanoma oncogene that confers resistance to BRAF inhibition

Abstract

Although targeting oncogenic mutations in the BRAF serine/threonine kinase with small molecule inhibitors can lead to significant clinical responses in melanoma, it fails to eradicate tumors in nearly all patients. Successful therapy will be aided by identification of intrinsic mechanisms that protect tumor cells from death. Here, we used a bioinformatics approach to identify drug-able, "driver" oncogenes restricted to tumor versus normal tissues. Applying this method to 88 short-term melanoma cell cultures, we show that the antiapoptotic BCL2 family member BCL2A1 is recurrently amplified in ∼30% of melanomas and is necessary for melanoma growth. BCL2A1 overexpression also promotes melanomagenesis of BRAFimmortalized melanocytes. We find that high-level expression of BCL2A1 is restricted to melanoma due to direct transcriptional control by the melanoma oncogene MITF. Although BRAF inhibitors lead to cell cycle arrest and modest apoptosis, we find that apoptosis is significantly enhanced by suppression of BCL2A1 in melanomas with BCL2A1 or MITF amplification. Moreover, we find that BCL2A1 expression is associated with poorer clinical responses to BRAF pathway inhibitors in melanoma patients. Cotreatment of melanomas with BRAF inhibitors and obatoclax, an inhibitor of BCL2A1 and other BCL2 family members, overcomes intrinsic resistance to BRAF inhibitors in BCL2A1-amplified cells in vitro and in vivo. These studies identify MITF-BCL2A1 as a lineage-specific oncogenic pathway in melanoma and underscore its role for improved response to BRAF-directed therapy.

Enhancer-targeted genome editing selectively blocks innate resistance to oncokinase inhibition

“…3). These results are consistent with other work implicating MITF in melanoma survival (Haq et al 2013) 754 Genome Research www.genome.org therefore regulates two contrary effects of BRAF inhibition, namely, induction of melanocyte differentiation, which is an anti-tumorigenic effect important for immune cell recognition of melanoma (Kono et al 2006;Boni et al 2010;Liu et al 2013), and the pro-tumorigenic effect of engaging innate drug resistance to BRAF inhibition.…”

Reversing drug resistance of soft tumor-repopulating cells by tumor cell-derived chemotherapeutic microparticles

“…Consistent with these findings, SCLCCs usually express high levels of anti-apoptotic proteins, DNA repair enzymes and ATP-binding cassette (ABC) transporters, which help SCLCCs survive the drug attack [6][7][8]. Thus, unraveling the roles of SCLCCs in tumorigenesis and drug resistance has changed our view on chemotherapy and aided the development of new therapeutic strategies against cancers [9][10][11]. Multiple signaling pathways, including WNT, TGF-β, Notch and Hedgehog pathways, have been found to play important roles in SCLCCs [12].…”

Coptidis Rhizoma induces intrinsic apoptosis through BAX and BAK activation in human melanoma

“…In contrast, BCL2A1 has been confirmed as a lineage-specific anti-apoptotic melanoma oncogene with amplification, which confers resistance to BRAF inhibition (29). In addition, BCL2A1 is also regulated by the melanoma-specific oncogene, MITF, which is also amplified specifically in melanoma UACC62 and UACC257 cells (30). In the present study, MITF mRNA and protein were also suppressed by CR (data not shown), supporting the functional significance of the MITF/BCL2A1 axis in CR-induced apoptosis.…”