P21‐activated kinase 1 regulates resistance to BRAF inhibition in human cancer cells

Abstract

BRAF is a commonly mutated oncogene in various human malignancies and a target of a new class of anti-cancer agents, BRAF-inhibitors (BRAFi). The initial enthusiasm for these agents, based on the early successes in the management of metastatic melanoma, is now challenged by the mounting evidence of intrinsic BRAFi-insensitivity in many BRAF-mutated tumors, by the scarcity of complete responses, and by the inevitable emergence of drug resistance in initially responsive cases. These setbacks put an emphasis on discovering the means to increase the efficacy of BRAFi and to prevent or overcome BRAFi-resistance. We explored the role of p21-activated kinases (PAKs), in particular PAK1, in BRAFi response. BRAFi lowered the levels of active PAK1 in treated cells. An activated form of PAK1 conferred BRAFi-resistance on otherwise sensitive cells, while genetic or pharmacologic suppression of PAK1 had a sensitizing effect. While activation of AKT1 and RAC1 proto-oncogenes increased BRAFi-tolerance, the protective effect was negated in the presence of PAK inhibitors. Furthermore, combining otherwise ineffective doses of PAK- and BRAF-inhibitors synergistically affected intrinsically BRAFi-resistant cells. Considering the high incidence of PAK1 activation in cancers, our findings suggests PAK inhibition as a strategy to augment BRAFi therapy and overcome some of the well-known resistance mechanisms.

IODVA1, a guanidinobenzimidazole derivative, targets Rac activity and Ras-driven cancer models

“…Sustained Ras signaling requires activation of cytoskeletal modifiers Rac and Rho, typically through the activation of their respective guanine nucleotide exchange factors [11][12][13][14][15]. The Rac/PAK pathway is involved in mechanisms of acquired drug resistance to BRAF monotherapy and BRAF+MEK combination therapy [16,17]. Thus, targeting a Raf-or PI3K-independent node in the Ras signaling network may provide another therapeutic option.…”

The role of PAK1 in the sensitivity of kidney epithelial cells to ischemia-like conditions

“…Pharmacological targeting of PAK1 is an area of active research [27], which is stimulated, in part, by numerous findings that PAK1 regulates survival and drug resistance in cancer (e.g. in melanoma [55,56]). While the role of PAK1 as a promoter of cell growth and survival has received a lot of attention, there are evidences that in certain contexts PAK1 participates in pro-apoptotic signaling [22][23][24].…”

“…The RNA interference reagents were obtained from the Genomics Shared Resource of the Roswell Park comprehensive Cancer Center. The viral constructs were used as reported elsewhere [55]. Trimetazidine, Aprepitant, U0126, IPA3 and AZD6244 were obtained from Selleck Chemicals (Houston, TX, USA).…”

“…L-733060 was from Tocris (Bristol, UK), PF3758309 was purchased from ChemieTek (Indianapolis, IN, USA). Cell numbers were compared using the methylene blue staining and extraction method as described [55].…”

PAK Kinase Inhibition Has Therapeutic Activity in Novel Preclinical Models of Adult T-Cell Leukemia/Lymphoma

“…Because cancers with aberrantly activated PAKs are often addicted to their activity (9) and PAK signaling can drive acquired drug resistance to targeted therapies in several types of cancers (17)(18)(19)(20), the PAK family kinases have been explored as therapeutic targets in a number of solid tumors and hematologic malignancies (18,19,21,22). In this study, we evaluated the therapeutic value of PAK inhibition in ATLL preclinical models.…”