In:
Cancer Research, American Association for Cancer Research (AACR), Vol. 75, No. 15_Supplement ( 2015-08-01), p. 2693-2693
Abstract:
MITF is a frequently amplified lineage-specific oncogene in human melanoma. Current drug discovery effort has, however, paradoxically ignored its criticality in melanoma cell biology and has failed to address MITF-associated intrinsic and acquired drug resistance. Here, to search the kinase targets able to circumvent the MITF-conferred intrinsic drug resistance, we used a multi-kinase inhibitor-directed chemical proteomics-based differential target affinity screen in immortalized human melanocytes carrying ectopic MITF overexpression. Through a subsequent methodical ‘gene expression-disease stage’ associations and a detailed functional interrogation in molecular-genetically diverse melanoma cellular systems, we identify a mitotic Ser/Thr kinase, Aurora Kinase A (AURKA) as a potential drug target in human melanoma that successfully overcomes MITF-engendered drug resistance phenotype. Critically, assessing the long-term efficacy of the phase II clinical trial approved highly specific AURKA-inhibitor MLN-8237, we pre-emptively witness a robust MAPK signalling-mediated immediate acquired resistance program involving MITF and Cyclin D1 induction through activity and expression changes in CREB and c-Jun respectively in both the BRAF- and NRAS-mut cells. Notably, identification of these ERK-directed acquired resistance mechanisms informed combinatorial AURKA/BRAF or AURKA/MEK targeting as an intelligent therapeutic strategy in BRAF- and NRAS-mut melanomas respectively. Citation Format: Gaurav Pathria, Bhavuk Garg, Kanika Garg, Viola Borgdorff, Christine Wagner, Giulio Superti-Furga, Stephan N. Wagner. Overcoming MITF-conferred resistance through dual AURKA/MAPK-axis targeting. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2693. doi:10.1158/1538-7445.AM2015-2693
Type of Medium:
Online Resource
ISSN:
0008-5472
,
1538-7445
DOI:
10.1158/1538-7445.AM2015-2693
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2015
detail.hit.zdb_id:
2036785-5
detail.hit.zdb_id:
1432-1
detail.hit.zdb_id:
410466-3
