Diving into the dark kinome to identify deadly therapeutic targets of RAS


When it comes to finding therapeutic targets for cancer, “mutated cancer genes are just the tip of the iceberg, but functional genomics can help unravel the larger, submerged part of the iceberg,” he explains. Dr. Christopher KempFred Hatch, Professor in the Department of Human Biology and Public Health Sciences. There is a focus on finding therapeutic treatments that target cancer-causing mutations, but in reality, “cancer cells have a lot of vulnerabilities beyond what people typically look for,” Dr. Kemp adds. The Kemp lab focuses on uncovering these vulnerabilities, or this submerged part of the iceberg, with a focus on investigating the “dark kinome.” The kinome refers to hundreds of kinases that play important roles in signaling and lead to the activation or inhibition of target proteins, yet the roles of many of these kinases remain poorly characterized. Cancer-causing mutations can rewire normal cellular functions and lead to dependence on certain kinases to help promote their unregulated growth. These kinases create vulnerabilities that are specific to cancer cells, as inhibiting one of these synthetic lethal kinases will only negatively affect the growth of cancer cells that have become dependent on them, while healthy cells remain largely unaffected.. In its recent publication Tumors Research paper, Kemp’s lab aims to exploit the cancer kinome and find target weak spots of cancer cells by identifying kinases required for cell growth in RAS-driven squamous cell carcinoma (SCC).

Mutations in RAS family members masher And the Brochure They occur frequently across a number of human cancers including SCC. However, despite decades of research, these cancers are still largely considered ineradicable as most of the putative targets that have been identified have failed to advance clinically. Rather than targeting these same mutant genes, Moser et al. sought to identify kinases in the oncogenic RAS signaling pathways that mutant RAS cells depend on for growth and survival. To do this, the researchers used a well-established, chemically induced SCC mouse model (through treatment with chemo-mutagenic DMBA and the tumor promoter TPA) that produces 80-90% of skin tumors containing a mutation in TPA. masher and to a lesser extent, Brochure. Since RAS genes in human cancers commonly co-evolve with DNA damage response genes, the researchers induced the RAS-driven SCC model in different mouse genetic backgrounds, some of which had an additional DNA damage response gene mutation such as Trp53 or ATM. The researchers then derived seven cell lineages from tumors with different genetic backgrounds from CSCs for use in their dark kinetic investigations. Taking a broad, unbiased approach, Kemp’s team performed an array siRNA screen in these seven CSCs-derived cell lines to eliminate approximately 600 kinase genes individually, rather than in bulk coordination. This design enabled researchers to identify cancer cell lines mutant for RAS kinases that normally depend on their growth, as well as investigate how these dependencies change when RAS mutant cells harbor an additional mutation in the DNA damage response pathway gene. While it takes a lot of work, asking how 600 kinases individually affect each of these different cell lines offers the advantage of a more reproducible and sensitive approach compared to dropping them all in a bulk fashion, which can often miss precise phenotypes. Screening of approximately 600 kinases in 7 different cell lines, in triplicate, results in a Many data. Kemp notes that one of the biggest challenges with this project was trying to figure out how to interpret all that data next.


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