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• W2912993305 abstract "Genetic and genomic studies of cancer cells have uncovered driving mutations that can in many cases be directly targeted to clinical benefit. The emergence of resistant cancer cells offers both an opportunity to dissect oncogenic and prosurvival cell-biologic pathways and a clear clinical need as resistance is a major cause of cancer mortality. Laboratory models and patient samples highlight resistance mechanisms that include: (i) direct alteration of small-molecule targets; (ii) activation of upstream or downstream signaling nodes; (iii) parallel signaling pathways to activate a common downstream pathway; (iv) epigenetic or transcriptionally effected histologic transformation; and (v) increasingly understood adaptive signaling changes that alter transcriptional cell states to promote survival. Understanding, predicting, and circumventing resistance to targeted cancer therapy is now a major endeavor for translational cancer biologists to undertake. Identification of the genomic drivers of cancer has led to the clinical development of targeted therapies that strike at the heart of many malignancies. Nonetheless, many cancers outsmart such precision-medicine efforts, and thus therapeutic resistance contributes significantly to cancer mortality. Attempts to understand the basis for resistance in patient samples and laboratory models has yielded two major benefits: one, more effective chemical inhibitors and rational combination therapies are now employed to prevent or circumvent resistance pathways; and two, our understanding of how oncogenic mutations drive cancer cell survival and oncogene addiction is deeper and broader, highlighting downstream or parallel cellular programs that shape these phenotypes. This review discusses emerging principles of resistance to therapies targeted against key oncogenic drivers. Identification of the genomic drivers of cancer has led to the clinical development of targeted therapies that strike at the heart of many malignancies. Nonetheless, many cancers outsmart such precision-medicine efforts, and thus therapeutic resistance contributes significantly to cancer mortality. Attempts to understand the basis for resistance in patient samples and laboratory models has yielded two major benefits: one, more effective chemical inhibitors and rational combination therapies are now employed to prevent or circumvent resistance pathways; and two, our understanding of how oncogenic mutations drive cancer cell survival and oncogene addiction is deeper and broader, highlighting downstream or parallel cellular programs that shape these phenotypes. This review discusses emerging principles of resistance to therapies targeted against key oncogenic drivers. a gene encoding the RTK UFO, which appears to be upregulated in a number of resistant cancer contexts. Its role in normal (i.e., nonmalignant) biology is as yet underexplored. a statistical model that incorporates both the prior probability of a given hypothesis being true based on earlier information and ongoing data that can support or refute that hypothesis, into a dynamic prediction of the likelihood of a hypothesis being true or not. one of three human rapidly accelerated fibrosarcoma (RAF) genes, which encodes a serine/threonine kinase that is activated by GTP-bound RAS and in turn activates MEK to activate ERK in the MAP kinase cascade. released under varying conditions into the bloodstream, but appears to be particularly elevated in the setting of cancer as well as in pregnancy (wherein it is derived from the developing fetus). The mechanisms controlling cfDNA secretion are still being explored. also known as ERBB1; one of four human EGFR (HER) family members. It is a RTK involved in epithelial patterning that is mutationally activated in subsets of NSCLC and glioblastoma and overexpressed in head and neck epithelial tumors. an observed phenotypic alteration whereby epithelial malignancies acquire a more mesenchymal histology and transcriptional profile. EMT is hypothesized to play a role both in cancer resistance and in metastatic potential. an amino acid in the ATP-binding pocket of kinases. Mutation of gatekeeper residues appears to widely block the activity of small-molecule kinase inhibitors through potentially multiple mechanisms including blocking access to the hydrophobic ATP-binding pocket, allosteric changes that increase intrinsic autophosphorylation kinase activity, and/or enhanced ATP affinity. Gatekeeper mutations associated with drug resistance include EGFR p.T790M and BCR-ABL1 p.T315I. a broad family including EGFR, HER2, ERBB3, and ERBB4. Heterodimerization of all family members is possible and is required for any activity arising from the kinase domain-deficient ERBB3. a RTK whose ligand is hepatocyte growth factor (HGF) [also called scatter factor (SF)] that normally plays a role in embryogenesis and organ patterning. MET can be activated by amplification or mutation in cancer. the MAP kinase cascade is a signaling module activated when GTP-bound RAS recruits RAF through its Ras-binding domain (RBD). RAF is thereby activated and kicks off a cascade of serine/threonine kinase activation including MEK and ERK. a transcription factor formed as a homo- or heterodimer of subunits including RELA, RELB, and others. NF-κB activity is implicated in a variety of cell-biologic functions including antiapoptosis and inflammation. the rat sarcoma oncogene is a small GTPase that cycles between an active, GTP-bound form and an inactive, GDP-bound form. When recruited to the cell membrane and active, RAS initiates signaling through multiple pathways to control the growth and survival of cells. The human genome encodes three RAS isoforms: NRAS, KRAS, and HRAS. Mutations in one of these three genes are present in up to a third of all cancers. a tumor-suppressor gene encoding the retinoblastoma (RB) protein, which binds to and sequesters E2F transcription factors, thus suppressing cell-cycle progression among other phenotypes. transmembrane proteins that bind to extracellular ligands, leading to the stimulation of their kinase activity. Activated RTKs can initiate intracellular signaling through multiple pathways. a tumor suppressor that encodes the P53 protein, a master regulator of the DNA-damage response. Loss of TP53 is common in cancer, and conversely, individuals with germline mutations in TP53 are affected by a significant cancer-predisposition condition known as Li–Fraumeni syndrome. small molecules that block the autophosphorylation and activation of protein tyrosine kinases. a signaling pathway discovered in Drosophila melanogaster, where its homolog wingless controls wing-bud development. In humans, the canonical WNT pathway is activated by extracellular WNT ligands that bind to the Frizzled family of transmembrane receptors, which in turn leads to the stabilization of beta catenin and its nuclear translocation to drive TCF/LEF transcription factor activity. WNT has been implicated in proliferation, migration, and cell fate or stemness. a transcriptional cofactor for the TEAD transcription factors. It is normally activated by Hippo signaling and through its control of cell growth and antiapoptotic targets can help to control organ size in normal development in response to cell–cell contact signals. It also appears to drive resistance to targeted MAP kinase inhibitors in a number of contexts." @default.
• W2912993305 created "2019-02-21" @default.
• W2912993305 creator A5004509086 @default.
• W2912993305 creator A5024176070 @default.
• W2912993305 date "2019-03-01" @default.
• W2912993305 modified "2023-10-18" @default.
• W2912993305 title "Principles of Resistance to Targeted Cancer Therapy: Lessons from Basic and Translational Cancer Biology" @default.
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• W2912993305 doi "https://doi.org/10.1016/j.molmed.2018.12.009" @default.
• W2912993305 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/6401263" @default.

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