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

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.

Precision unveiled: Synergistic genomic landscapes in breast cancer—Integrating single‐cell analysis and decoding drug toxicity for elite prognostication and tailored therapeutics

“…Linsitinib currently for hormone‐sensitive breast cancer there are studies combining endocrine therapy and erlotinib as a treatment option 90 . Gemcitabine, as a potent anti‐tumor drug, metastatic triple‐negative breast cancer, pancreatic ductal adenocarcinoma, and other cancers are used in Reference 91 Alisertib has also been used in the tumor subtypes with HER2 Demonstrating some effect 92 …”

“…Linsitinib currently for hormone-sensitive breast cancer there are studies combining endocrine therapy and erlotinib as a treatment option 90. Gemcitabine, as a potent anti-tumor drug, metastatic triple-negative breast cancer, pancreatic ductal adenocarcinoma, and other cancers are used in Reference 91 Alisertib has also been used in the tumor subtypes with HER2 Demonstrating some effect 92. Of particular interest is the robust affinity observed between Vorinostat and HNRNPR, registering a binding energy of À101.475.GivenHNRNPR's crucial influence on tumoral proliferation and metastasis and considering that Vorinostat is primarily prescribed for T-cell lymphomas, this finding is intriguing.…”