title: Inhibition of PI3K/mTOR leads to adaptive resistance in matrix-attached cancer cells.
abstract: The PI3K/mTOR-pathway is the most commonly dysregulated pathway in epithelial cancers and represents an important target for cancer therapeutics. Here, we show that dual inhibition of PI3K/mTOR in ovarian cancer-spheroids leads to death of inner matrix-deprived cells, whereas matrix-attached cells are resistant. This matrix-associated resistance is mediated by drug-induced upregulation of cellular survival programs that involve both FOXO-regulated transcription and cap-independent translation. Inhibition of any one of several upregulated proteins, including Bcl-2, EGFR, or IGF1R, abrogates resistance to PI3K/mTOR inhibition. These results demonstrate that acute adaptive responses to PI3K/mTOR inhibition in matrix-attached cells resemble well-conserved stress responses to nutrient and growth factor deprivation. Bypass of this resistance mechanism through rational design of drug combinations could significantly enhance PI3K-targeted drug efficacy.
authors.affiliation: Department of Cell Biology, Harvard Medical School, 240 Longwood Avenue, Boston, MA 02115, USA.
authors.forename: Taru
authors.initials: T
authors.lastname: Muranen
authors.forename: Laura M
authors.initials: LM
authors.lastname: Selfors
authors.forename: Devin T
authors.initials: DT
authors.lastname: Worster
authors.forename: Marcin P
authors.initials: MP
authors.lastname: Iwanicki
authors.forename: Loling
authors.initials: L
authors.lastname: Song
authors.forename: Fabiana C
authors.initials: FC
authors.lastname: Morales
authors.forename: Sizhen
authors.initials: S
authors.lastname: Gao
authors.forename: Gordon B
authors.initials: GB
authors.lastname: Mills
authors.forename: Joan S
authors.initials: JS
authors.lastname: Brugge
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001943:Breast Neoplasms / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology; D018797:Cell Cycle Proteins; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000037:antagonists & inhibitors; D005109:Extracellular Matrix / Q000187:drug effects; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D051379:Mice; D010051:Ovarian Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010750:Phosphoproteins; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors; D011804:Quinolines / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors; D015398:Signal Transduction; D013312:Stress, Physiological; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D014183:Transplantation, Heterologous
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; C087000:EIF4EBP1 protein, human; D007093:Imidazoles; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010750:Phosphoproteins; D019253:Proto-Oncogene Proteins c-bcl-2; D011804:Quinolines; D012333:RNA, Messenger; D066246:ErbB Receptors; D017526:Receptor, IGF Type 1; D058570:TOR Serine-Threonine Kinases; C531198:dactolisib