Coordinated dysregulation of cancer progression by the HER family and p21-activated kinases
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Coordinated dysregulation of cancer progression by the HER family and p21-activated kinases Rakesh Kumar 1,2,3 & Aswathy Mary Paul 1,4 & Ravikumar Amjesh 1 & Bijesh George 1,4 & M. Radhakrishna Pillai 1 Received: 24 July 2020 / Accepted: 25 July 2020 # Springer Science+Business Media, LLC, part of Springer Nature 2020
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 HER3HER2 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. Keywords Cancer . EGFR family . PAKs . Signaling . Polygenic disease . Gene expression
1 Introduction The neoplastic transformation, progression, and maintenance of cancerous phenotypes are driven by dysregulation of multiple core regulatory pathways, including hyper- and/or persistent stimulation of cellular processes such as mitogenic signaling, cytoskeleton remodeling favoring directional migration for a * Rakesh Kumar [email protected] * M. Radhakrishna Pillai [email protected] 1
Cancer Research Program, Rajiv Gandhi Centre for Biotechnology, Trivandrum, Kerala, India
2
Department of Medicine, Division of Hematology & Oncology, Rutgers New Jersey Medical School, Newark, NJ, USA
3
Department of Human and Molecular Genetics, Virginia Commonwealth University Medical Center, Richmond, VA, USA
4
PhD Program in Biotechnology, Manipal Academy of Higher Education, Manipal, India
productive invasion, and signaling-dependent gene expression. At the molecular level, human canc
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