title: A New View of Pathway-Driven Drug Resistance in Tumor Proliferation.
abstract: Defeating drug resistance in tumor cell proliferation is challenging. We propose that signaling in cell proliferation takes place via two core pathways, each embodying multiple alternative pathways. We consider drug resistance through an alternative proliferation pathway - within the same or within the other core pathway. Most drug combinations target only one core pathway; blocking both can restrain proliferation. We define core pathways as independent and acting similarly in cell-cycle control, which can explain why their products (e.g., ERK and YAP1) can substitute for each other in resistance. Core pathways can forecast possible resistance because acquired resistance frequently occurs through alternative proliferation pathways. This concept may help to predict the efficacy of drug combinations. The selection of distinct combinations for specific mutated pathways would be guided by clinical diagnosis.
authors.affiliation: Cancer and Inflammation Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, National Cancer Institute at Frederick, Frederick, MD 21702, USA; Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel. Electronic address: nussinor@helix.nih.gov.
authors.forename: Ruth
authors.initials: R
authors.lastname: Nussinov
authors.affiliation: Cancer and Inflammation Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, National Cancer Institute at Frederick, Frederick, MD 21702, USA.
authors.forename: Chung-Jung
authors.initials: CJ
authors.lastname: Tsai
authors.affiliation: Cancer and Inflammation Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, National Cancer Institute at Frederick, Frederick, MD 21702, USA.
authors.forename: Hyunbum
authors.initials: H
authors.lastname: Jang
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction
chemical_list: D000970:Antineoplastic Agents
keywords: K-Ras; KRAS; MAPK; PI3K; RAS; signaling pathways