APHON Pediatric Chemotherapy-Biotherapy Renewal

Another example of an intracellular signaling pathway is the PI3K/ATK/mTOR pathway. Many types of cancer take over this pathway to promote their abnormal cell growth. Temsirolimus is a small molecule inhibitor that affects the mTOR receptor in this pathway, causing “decreased expression of mRNAs necessary for cell cycle progression and arresting cells in the G 1 phase of the cell cycle” (National Center for Biotechnology Information, 2021, “Summary”). Tyrosine kinase inhibitors target signaling proteins that control cell growth and differentiation. Examples of tyrosine kinase inhibitors are imatinib, dasatinib, and nilotinib. This family of agents is most often used in the treatment of BCR-ABL1-positive leukemias. The JAK/STAT pathway regulates cell growth, survival, and differentiation. Ruxolitinib is a small molecule inhibitor that targets this pathway and is currently being evaluated for use against pediatric leukemias that have a JAK mutation. Ubiquitin-Proteasome System The proteasome is a large multiprotein complex in the ubiquitin-proteasome system that is responsible for cell protein degradation, therefore playing a role in cell survival and signaling. Because cancer cells have a high protein turnover rate, they are particularly sensitive to proteasome inhibition. Bortezomib was the first proteasome inhibitor used in clinical trials; it has since been found to be more effective when used with additional chemotherapeutic agents (Kuhlen et al., 2019).