PAK1 and Therapy Resistance in Melanoma

Abstract

Malignant melanoma claims more lives than any other skin malignancy. While primary melanomas are usually cured via surgical excision, the metastatic form of the disease portents a poor prognosis. Decades of intense research has yielded an extensive armamentarium of anti-melanoma therapies, ranging from genotoxic chemo- and radiotherapies to targeted interventions in specific signaling pathways and immune functions. Unfortunately, even the most up-to-date embodiments of these therapies are not curative for the majority of metastatic melanoma patients, and the need to improve their efficacy is widely recognized. Here, we review the reports that implicate p21-regulated kinase 1 (PAK1) and PAK1-related pathways in the response of melanoma to various therapeutic modalities. Ample data suggest that PAK1 may decrease cell sensitivity to programmed cell death, provide additional stimulation to growth-promoting molecular pathways, and contribute to the creation of an immunosuppressive tumor microenvironment. Accordingly, there is mounting evidence that the concomitant inhibition of PAK1 enhances the potency of various anti-melanoma regimens. Overall, the available information suggests that a safe and effective inhibition of PAK1-dependent molecular processes would enhance the potency of the currently available anti-melanoma treatments, although considerable challenges in implementing such strategies still exist.

Keywords: PAK1; RAC1; acral melanoma; chemotherapy; cutaneous melanoma; immune therapy; targeted therapy; uveal melanoma.

Figure 2

PAK1 structure and position within human kinome. (A) Conserved elements within PAK1 isoforms 1 and 2. (B) Position of PAK proteins on the evolutionary tree of human kinases. The evolutionary tree of kinases was drawn using KinMap [31].

Figure 2

PAK1 structure and position within human kinome. (A) Conserved elements within PAK1 isoforms 1 and 2. (B) Position of PAK proteins on the evolutionary tree of human kinases. The evolutionary tree of kinases was drawn using KinMap [31].

Figure 1

Proposed mechanisms linking PAK1 activity and melanoma resistance to various therapeutic modalities. See text for details.

Figure 3

Examples of synergistic suppression of uveal melanoma cells via combinations of PAK inhibitors and a MEK inhibitor, selumetinib. Mel202 uveal melanoma cells [115] (a gift from Dr. Harbour, University of Texas Southwestern) were exposed to a range of doses of selumetinib in combination with various doses of PAK inhibitors PF3758309 (A) or IPA3 (B). After 5 days of treatment, the numbers of remaining cells were compared using methylene blue staining and an extraction method as described earlier [116], and drug synergy according to the Bliss synergy model was analyzed using SynegyFinder software (version #: 6.04.2023-R-3.6.3-dev) [117].