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A Method for Screening and Validation of Resistant Mutations Against Kinase Inhibitors
Published on: December 7, 2014
Hyperactivation of p21-Activated Kinases in Human Cancer and Therapeutic Sensitivity
Deivendran Sankaran1, Revikumar Amjesh2, Aswathy Mary Paul3
1Signal Transduction and Molecular Pharmacology, The Institute of Cancer Research, London SW7 3RP, UK.
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.
Insights
p21-activated kinases (PAKs) promote cancer growth and resistance to therapy. Targeting PAKs, alongside other treatments, may enhance anticancer effects by overcoming compensatory survival pathways.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Signaling
Background:
- p21-activated kinases (PAKs) are intracellular signaling molecules implicated in cancer progression.
- PAKs regulate key cancer hallmarks including cell survival, growth, and invasiveness.
- Overexpression and hyperactivation of PAKs are observed in numerous human tumors, establishing them as therapeutic targets.
Purpose of the Study:
- To review the role of PAKs in cancer cell signaling.
- To discuss PAKs as therapeutic targets for cancer treatment.
- To explore the involvement of PAKs in therapeutic resistance and potential co-targeting strategies.
Main Methods:
- Literature review of studies on PAKs in cancer.
- Analysis of PAK signaling pathways in cancer progression.
- Examination of PAK inhibitors and their clinical relevance.
- Investigation of PAKs' role in mediating resistance to anticancer drugs.
Main Results:
- PAKs exhibit diverse cancer-promoting functions, including survival and invasiveness.
- PAKs are validated therapeutic targets, with several inhibitors developed.
- Inhibition of one PAK member can lead to compensatory activation of others.
- PAKs are activated by anticancer drugs and contribute to therapeutic resistance.
Conclusions:
- PAKs play a critical role in cancer cell survival and therapeutic resistance.
- Compensatory activation of PAKs presents a challenge for monotherapy.
- Co-targeting PAKs with other agents offers a promising strategy to enhance anticancer efficacy and overcome resistance.
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