Hyperactivation of p21-Activated Kinases in Human Cancer and Therapeutic Sensitivity

Author:

Sankaran Deivendran1,Amjesh Revikumar2ORCID,Paul Aswathy Mary3,George Bijesh3,Kala Rajat4,Saini Sunil4,Kumar Rakesh456

Affiliation:

1. Signal Transduction and Molecular Pharmacology, The Institute of Cancer Research, London SW7 3RP, UK

2. Centre for Integrative Omics Data Science, Yenepoya (Deemed to be) University, Mangalore 578018, India

3. Cancer Research Program, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram 695014, India

4. Cancer Research Institute, Himalayan Institute of Medical Sciences, Swami Rama Himalayan University, Dehradun 248016, India

5. Department of Medicine-Hematology and Oncology, Rutgers New Jersey Medical School, Newark, NJ 07103, USA

6. Department of Human and Molecular Genetics, School of Medicine, Virginia Commonwealth University, Richmond, VA 23298, USA

Abstract

Over the last three decades, p21-activated kinases (PAKs) have emerged as prominent intracellular nodular signaling molecules in cancer cells with a spectrum of cancer-promoting functions ranging from cell survival to anchorage-independent growth to cellular invasiveness. As PAK family members are widely overexpressed and/or hyperactivated in a variety of human tumors, over the years PAKs have also emerged as therapeutic targets, resulting in the development of clinically relevant PAK inhibitors. Over the last two decades, this has been a promising area of active investigation for several academic and pharmaceutical groups. Similar to other kinases, blocking the activity of one PAK family member leads to compensatory activity on the part of other family members. Because PAKs are also activated by stress-causing anticancer drugs, PAKs are components in the rewiring of survival pathways in the action of several therapeutic agents; in turn, they contribute to the development of therapeutic resistance. This, in turn, creates an opportunity to co-target the PAKs to achieve a superior anticancer cellular effect. Here we discuss the role of PAKs and their effector pathways in the modulation of cellular susceptibility to cancer therapeutic agents and therapeutic resistance.

Publisher

MDPI AG

Subject

General Biochemistry, Genetics and Molecular Biology,Medicine (miscellaneous)

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