pf-3758309 and Breast-Neoplasms

LIM kinase 1 (LIMK1) and p21-activated kinase 4 (PAK4) are often over-expressed in breast tumors, which causes aggressive cancer phenotypes and unfavorable clinical outcomes. In addition to the well-defined role in regulating cell division, proliferation and invasion, the two kinases promote activation of the MAPK pathway and cause endocrine resistance through phosphorylating estrogen receptor alpha (ERα). PAK4 specifically phosphorylates LIMK1 and its functional partners, indicating possible value of suppressing both kinases in cancers that over-express PAK4 and/or LIMK1. Here, for the first time, we assessed the impact of combining LIMK1 inhibitor LIMKi 3 and PAK4 inhibitor PF-3758309 in preclinical breast cancer models. LIMK1 and PAK4 pharmacological inhibition synergistically reduced the survival of various cancer cell lines, exhibiting specific efficacy in luminal and HER2-enriched models, and suppressed development and ERα-driven signals in a BT474 xenograft model. In silico analysis demonstrated the cell lines with reliance on LIMK1 were the most prone to be susceptible to PAK4 inhibition. Double LIMK1 and PAK4 targeting therapy can be a successful therapeutic strategy for breast cancer, with a unique efficiency in the subtypes of luminal and HER2-enriched tumors.

Topics: Animals; Breast Neoplasms; Cell Line, Tumor; Cell Survival; Drug Synergism; Female; Gene Expression Regulation, Neoplastic; Humans; Lim Kinases; MAP Kinase Signaling System; Mice; p21-Activated Kinases; Phosphorylation; Pyrazoles; Pyrroles; Thiazoles; Xenograft Model Antitumor Assays

p21-Activated kinase-1 (Pak1) is frequently upregulated in human breast cancer and is required for transformation of mammary epithelial cells by ErbB2. Here, we show that loss of Pak1, but not the closely related Pak2, leads to diminished expression of β-catenin and its target genes. In MMTV-ErbB2 transgenic mice, loss of Pak1 prolonged survival, and mammary tissues of such mice showed loss of β-catenin. Expression of a β-catenin mutant bearing a phospho-mimetic mutation at Ser 675, a specific Pak1 phosphorylation site, restored transformation to ErbB2-positive, Pak1-deficient mammary epithelial cells. Mice bearing xenografts of ErbB2-positive breast cancer cells showed tumor regression when treated with small-molecule inhibitors of Pak or β-catenin, and combined inhibition by both agents was synergistic. These data delineate a signaling pathway from ErbB2 to Pak to β-catenin that is required for efficient transformation of mammary epithelial cells, and suggest new therapeutic strategies in ErbB2-positive breast cancer.

Topics: Animals; Apoptosis; beta Catenin; Blotting, Western; Breast Neoplasms; Cell Line; Cell Line, Tumor; Cell Proliferation; Cell Survival; Cell Transformation, Neoplastic; Dose-Response Relationship, Drug; Epithelial Cells; Humans; Mice; Mice, Inbred ICR; Mice, Knockout; Mice, SCID; Mice, Transgenic; p21-Activated Kinases; Pyrazoles; Pyrroles; Receptor, ErbB-2; RNA Interference; Xenograft Model Antitumor Assays