Coordinated dysregulation of cancer progression by the HER family and p21-activated kinases

Abstract

Most epithelial cancer types are polygenic in nature and are driven by coordinated dysregulation of multiple regulatory pathways, genes, and protein modifications. The process of coordinated regulation of cancer promoting pathways in response to extrinsic and intrinsic signals facilitates the dysregulation of several pathways with complementary functions, contributing to the hallmarks of cancer. Dysregulation and hyperactivation of cell surface human epidermal growth factor receptors (HERs) and cytoskeleton remodeling by p21-activated kinases (PAKs) are two prominent interconnected aspects of oncogenesis. We briefly discuss the discoveries and significant advances in the area of coordinated regulation of HERs and PAKs in the development and progression of breast and other epithelial cancers. We also discuss how initial studies involving heregulin signaling via HER3-HER2 axis and HER2-overexpressing breast cancer cells not only discovered a mechanistic role of PAK1 in breast cancer pathobiology but also acted as a bridge in generating a broader cancer research interest in other PAK family members and cancer types and catalyzed establishing the role of PAKs in human cancer, at-large. In addition, growth factor stimulation of the PAK pathway also helped to recognize new facets of PAKs, connecting the PAK pathway to oncogenesis, nuclear signaling, gene expression, mitotic progression, DNA damage response, among other phenotypic responses, and shaped the field of PAK cancer research. Finally, we recount some of the current limitations of HER-and PAK-directed therapeutics in counteracting acquired therapeutic resistance and discuss how cancer's as a polygenic disease may be best targeted with a polygenic approach.

PAK1 overexpression promotes myxofibrosarcoma angiogenesis through STAT5B-mediated CSF2 transactivation: clinical and therapeutic relevance of amplification and nuclear entry

“…Using confocal immunofluorescence microscopy, we observed varying but distinctive nuclear PAK1 localization in parent myxofibrosarcoma cells ( Figure-S6A ), commensurate with significant nuclear PAK1 immunoexpression in a subset of aggressive myxofibrosarcomas detailed below. PAK1 signaling may modulate angiogenesis through multiple pathways, including generation of tumor-derived secreted factors in cancer cells or stimulation of the endothelium-specific PAK1 activation in endothelial cells 13 , 19 , 25 , 26 . Our in vitro evidence indicated that CSF2 is a potential PAK1-driven angiogenic factor self-produced by myxofibrosarcoma cells ( Figure- 2 ).…”

“…However, the clinical and functional relevance of PAK1 and associated signaling remains undefined in myxofibrosarcoma. Compared with RSF1, PAK1, the prototypical member of p21-activating kinase family, is relatively feasible as a direct therapeutic target, since PAK1 functions as a cytosolic molecular hub converging upstream signals mediated by RhoGTPases to integrate various mitogenic and morphogenetic inputs and transcriptionally co-regulate expression of target genes upon nuclear relocation [12][13][14][15][16][17][18][19].…”

P21 Overexpression Promotes Cell Death and Induces Senescence in Human Glioblastoma

“…Since P21 is downstream to p53 which is frequently mutated in cancer, P21 activity can be dysregulated in cancer. Indeed, some studies have suggested that P21 can paradoxically promote proliferation in cancer cells under certain conditions [26,27,28,29,30]. We directly manipulated P21 in both P53-mutant (GBM6) and P53-WT cells with (GBM164) and without (GBM39) IDH-mutation and observed that P21-induced apoptosis and senescence in surviving cells in each cell line.…”

Afatinib Treatment Alone or with Bevacizumab in a Real-World Cohort of Non-Small Cell Lung Cancer Patients with Epidermal Growth Factor Receptor Mutation

“…On the other hand, the mechanism of action of the two therapies may have a certain overlap. Previous studies have revealed that neuregulin-dependent ErbB3 and ErbB4 signaling in cancer cells contributed to VEGF-mediated angiogenesis and anti-apoptosis [ 28 , 29 , 30 , 31 ]. Furthermore, non-cancerous stromal cell- or vascular endothelial cell-derived neuregulin also promoted angiogenesis and VEGF expression via ErbB3 and ErbB4 in an autocrine or paracrine manner [ 32 , 33 ].…”