Abstract 195: Defining the role of PAK7 variants in melanoma

• Published in: Cancer research (Chicago, Ill.) Vol. 76; no. 14_Supplement; p. 195
• Main Authors: LaPak, Kyle M., Gross, Michael A., Vroom, Denny C., Lesinski, Greg B., Carson, William E., Burd, Christin E.
• Format: Journal Article
• Language: English
• Published: 15.07.2016
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/1538-7445.AM2016-195

Abstract Melanoma mortality is directly linked to its profoundly metastatic nature and inherent resistance to conventional chemotherapy. For this reason, increased understanding of the molecular mechanisms driving melanoma progression is of utmost importance. The p21-activated serine/threonine kinases (PAKs) are frequently mutated or overexpressed in cancer and have recently been implicated in tumor metastasis, proliferation, and apoptotic resistance. This observation has inspired drug discovery efforts to limit PAK activity; yet, mechanistic understanding of how PAKs (especially Type II PAKs) contribute to tumor initiation and progression is still evolving. PAK7, a type II PAK, is mutated in 16-18% of all melanomas. Melanoma-associated PAK7 mutations occur throughout the gene and have unknown biochemical and physiological consequences. The objective of this study was to determine how tumor-associated PAK7 variants mechanistically contribute to melanoma initiation and progression. First, we characterized PAK7 protein expression in a panel of 39 melanoma cell lines and primary melanocyte cultures. PAK7 levels were similar in both tumorigenic and non-tumorigenic cells and failed to correlate with the status of common melanoma driver mutations (e.g. NRASQ61, BRAFV600). In an array of 101 human tumor biopsies, PAK7 expression did not significantly change with advancing melanoma stage; however, PAK7 levels were higher in regional lymph node biopsies when compared to primary skin lesions. Since mutation is the predominant mechanism affecting PAK7 in melanoma, we investigated the biochemical and physiological consequences of common PAK7 variants. 11 distinct PAK7 mutations were stably expressed at low levels in VMM39 (melanoma) and NCI-H441 (lung) cells. Using these clones, changes in the phosphorylation of downstream PAK7 targets associated with cellular migration (p120), proliferation (CRAF), and apoptotic resistance (BAD, MDM2) were examined. In addition, we defined phenotypic alterations in cellular morphology, proliferation, migration, and apoptotic resistance associated with the expression of each mutant. These data allowed us to classify PAK7 variants of unknown significance into groups associated with specific cellular outcomes. To our knowledge, this is the first study to functionally characterize a wide variety of melanoma-associated PAK7 mutations and represents a critical first step in understanding how this kinase contributes to tumor initiation and progression. Citation Format: Kyle M. LaPak, Michael A. Gross, Denny C. Vroom, Greg B. Lesinski, William E. Carson. Defining the role of PAK7 variants in melanoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 195.