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

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.

The Revelation of Continuously Organized, Co-Overexpressed Protein-Coding Genes with Roles in Cellular Communications in Breast Cancer.

Many human cancers, including breast cancer, are polygenic and involve the co-dysregulation of multiple regulatory molecules and pathways. Though the overexpression of genes and amplified chromosomal regions have been closely linked in breast cancer, the notion of the co-upregulation of genes at a single locus remains poorly described. Here, we describe the co-overexpression of 34 continuously organized protein-coding genes with diverse functions at 8q.24.3(143437655-144326919) in breast and other cancer types, the CanCord34 genes. In total, 10 out of 34 genes have not been reported to be overexpressed in breast cancer. Interestingly, the overexpression of CanCord34 genes is not necessarily associated with genomic amplification and is independent of hormonal or HER2 status in breast cancer. CanCord34 genes exhibit diverse known and predicted functions, including enzymatic activities, cell viability, multipotency, cancer stem cells, and secretory activities, including extracellular vesicles. The co-overexpression of 33 of the CanCord34 genes in a multivariant analysis was correlated with poor survival among patients with breast cancer. The analysis of the genome-wide RNAi functional screening, cell dependency fitness, and breast cancer stem cell databases indicated that three diverse overexpressed CanCord34 genes, including a component of spliceosome PUF60, a component of exosome complex EXOSC4, and a ribosomal biogenesis factor BOP1, shared roles in cell viability, cell fitness, and stem cell phenotypes. In addition, 17 of the CanCord34 genes were found in the microvesicles (MVs) secreted from the mesenchymal stem cells that were primed with MDA-MB-231 breast cancer cells. Since these MVs were important in the chemoresistance and dedifferentiation of breast cancer cells into cancer stem cells, these findings highlight the significance of the CanCord34 genes in cellular communications. In brief, the persistent co-overexpression of CanCord34 genes with diverse functions can lead to the dysregulation of complementary functions in breast cancer. In brief, the present study provides new insights into the polygenic nature of breast cancer and opens new research avenues for basic, preclinical, and therapeutic studies in human cancer.

Evidence of a dysregulated vitamin D endocrine system in SARS-CoV-2 infected patient's lung cells.

Although a defective vitamin D endocrine system has been widely suspected to be associated in SARS-CoV-2 pathobiology, the status of the vitamin D endocrine system and vitamin D-modulated genes in lung cells of patients infected with SARS-CoV-2 remains unknown. To understand the significance of the vitamin D endocrine system in SARS-CoV-2 pathobiology, computational approaches were applied to transcriptomic datasets from bronchoalveolar lavage fluid (BALF) cells of such patients or healthy individuals. Levels of vitamin D receptor, retinoid X receptor, and CYP27A1 in BALF cells of patients infected with SARS-CoV-2 were found to be reduced. Additionally, 107 differentially expressed, predominantly downregulated genes, as potentially modulated by vitamin D endocrine system, were identified in transcriptomic datasets from patient's cells. Further analysis of differentially expressed genes provided eight novel genes with a conserved motif with vitamin D-responsive elements, implying the role of both direct and indirect mechanisms of gene expression by the dysregulated vitamin D endocrine system in SARS-CoV-2-infected cells. Protein-protein interaction network of differentially expressed vitamin D-modulated genes were enriched in the immune system, NF-κB/cytokine signaling, and cell cycle regulation as top predicted pathways that might be affected in the cells of such patients. In brief, the results presented here povide computational evidence to implicate a dysregulated vitamin D endocrine system in the pathobiology of SARS-CoV-2 infection.

Cellular Fitness Phenotypes of Cancer Target Genes from Oncobiology to Cancer Therapeutics.

To define the growing significance of cellular targets and/or effectors of cancer drugs, we examined the fitness dependency of cellular targets and effectors of cancer drug targets across human cancer cells from 19 cancer types. We observed that the deletion of 35 out of 47 cellular effectors and/or targets of oncology drugs did not result in the expected loss of cell fitness in appropriate cancer types for which drugs targeting or utilizing these molecules for their actions were approved. Additionally, our analysis recognized 43 cellular molecules as fitness genes in several cancer types in which these drugs were not approved, and thus, providing clues for repurposing certain approved oncology drugs in such cancer types. For example, we found a widespread upregulation and fitness dependency of several components of the mevalonate and purine biosynthesis pathways (currently targeted by bisphosphonates, statins, and pemetrexed in certain cancers) and an association between the overexpression of these molecules and reduction in the overall survival duration of patients with breast and other hard-to-treat cancers, for which such drugs are not approved. In brief, the present analysis raised cautions about off-target and undesirable effects of certain oncology drugs in a subset of cancers where the intended cellular effectors of drug might not be good fitness genes and that this study offers a potential rationale for repurposing certain approved oncology drugs for targeted therapeutics in additional cancer types.