Abstract 22: Overexpression of PAK 1 is a favorable prognostic biomarker in malignant melanoma.

Abstract

Abstract The incidence of malignant melanoma, the most lethal form of skin cancer, is increasing. Approximately 76,000 new cases of invasive melanoma and 9,000 deaths from the disease are anticipated in 2012. Melanoma, a heterogeneous and multistep disease, is one of the most frequent cancers in young adults 20-30 years of age. Identification of prognostic factors for melanoma patients and a better understanding of melanoma progression are needed. An initial radial growth phase of melanomas is followed by a vertical growth phase. Although metastatic capacity is thought to be acquired during the vertical growth phase, metastases occur in some patients with primary melanomas having a radial growth pattern. In this study of 40 melanoma patients we examined immunohistochemically detected cytoplasmic and nuclear expression of p21-activated kinase 1 (PAK 1) in FFPE archived surgical specimens of the four major subtypes of cutaneous melanoma (superficial spreading melanoma, nodular melanoma, lentigo maligna melanoma, and acral lentiginous melanoma), as well as benign nevi and normal skin, in relation to clinical outcome. The highest expression of both nuclear and cytoplasmic PAK 1 was found in superficial spreading melanomas (which comprise 70% of melanoma cases in the US) and was significantly increased relative to normal skin (P < 0.0001). High nuclear and cytoplasmic expression of PAK 1 relative to normal skin was found in some (8-17%) of the other forms of melanoma. Overexpression of PAK 1 was not found in lymph node or lung metastases from 13 patients. Overexpression of cytoplasmic PAK 1 in the primary tumors from 28 patients was associated with increased survival (P = 0.03). Only 25% of patients with uniformly high (3+) cytoplasmic expression of PAK 1 in their primary tumor died compared to 67% of patients with less cytoplasmic PAK 1. Similarly only 22% of patients with more than trace expression of PAK 1 in 50% of the nuclei in their primary tumor died compared to 61% of patients with less nuclear PAK 1. The difference in survival between 28 patients with high and low nuclear PAK 1 in their primary tumor approached significance (P = 0.062). Overall, patients with superficial spreading melanoma had not only the highest cytoplasmic and nuclear PAK 1 expression in their tumor, but also tended to have better survival than patients with other forms of melanoma (P = 0.07). PAK 1 has multiple cellular effects including effects on growth factor signaling, cytoskeletal signaling, oncogenic transformation and survival, and chromatin and nuclear signaling. Our data indicate that PAK 1 overexpression in primary melanomas portends increased survival for the melanoma patient, possibly reflecting the relevance of PAK 1 to the radial vs. the vertical phase of melanoma progression. Citation Format: Julia H. Carter, Nelson R. Spaulding, Bruce M. Colligan, James A. Deddens, Larry E. Douglass. Overexpression of PAK 1 is a favorable prognostic biomarker in malignant melanoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 22. doi:10.1158/1538-7445.AM2013-22