title: Drug resistance via feedback activation of Stat3 in oncogene-addicted cancer cells.
abstract: Pathway-targeted cancer drugs can produce dramatic responses that are invariably limited by the emergence of drug-resistant cells. We found that many drug-treated "oncogene-addicted" cancer cells engage a positive feedback loop leading to Stat3 activation, consequently promoting cell survival and limiting overall drug response. This was observed in cancer cells driven by diverse activated kinases, including EGFR, HER2, ALK, and MET, as well as mutant KRAS. Specifically, MEK inhibition led to autocrine activation of Stat3 via the FGF receptor and JAK kinases, and pharmacological inhibition of MEK together with JAK and FGFR enhanced tumor regression. These findings suggest that inhibition of a Stat3 feedback loop may augment the response to a broad spectrum of drugs that target pathways of oncogene addiction.
authors: Department of Discovery Oncology, Genentech, 1 DNA Way, South San Francisco, CA 94080, USA.
authors: Ho-June
authors: HJ
authors: Lee
authors: Department of Discovery Oncology, Genentech, 1 DNA Way, South San Francisco, CA 94080, USA.
authors: Guanglei
authors: G
authors: Zhuang
authors: Department of Bioinformatics, Genentech, 1 DNA Way, South San Francisco, CA 94080, USA.
authors: Yi
authors: Y
authors: Cao
authors: Department of Bioinformatics, Genentech, 1 DNA Way, South San Francisco, CA 94080, USA.
authors: Pan
authors: P
authors: Du
authors: Department of Discovery Oncology, Genentech, 1 DNA Way, South San Francisco, CA 94080, USA.
authors: Hyo-Jin
authors: HJ
authors: Kim
authors: Department of Discovery Oncology, Genentech, 1 DNA Way, South San Francisco, CA 94080, USA. Electronic address: settleman.jeffrey@gene.com.
authors: Jeff
authors: J
authors: Settleman
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000378:metabolism* / Q000401:mortality; D000077192:Adenocarcinoma of Lung; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism; D000069347:Erlotinib Hydrochloride; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D015850:Interleukin-6 / Q000378:metabolism; D053613:Janus Kinase 1 / Q000378:metabolism; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000401:mortality; D051379:Mice; D016513:Mice, SCID; D009154:Mutation; D009570:Nitriles; D009857:Oncogenes; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras); D011720:Pyrazoles / Q000494:pharmacology; D011724:Pyridazines / Q000494:pharmacology; D011743:Pyrimidines; D011799:Quinazolines / Q000494:pharmacology; D017468:Receptors, Fibroblast Growth Factor / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction; D023041:Xenograft Model Antitumor Assays; D018631:ras Proteins / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents; D066246:ErbB Receptors; D000069347:Erlotinib Hydrochloride; D007093:Imidazoles; D015850:Interleukin-6; D053613:Janus Kinase 1; D009570:Nitriles; D019869:Phosphatidylinositol 3-Kinases; D011518:Proto-Oncogene Proteins; D016283:Proto-Oncogene Proteins p21(ras); D011720:Pyrazoles; D011724:Pyridazines; D011743:Pyrimidines; D011799:Quinazolines; D017468:Receptors, Fibroblast Growth Factor; D050796:STAT3 Transcription Factor; D018631:ras Proteins; C508600:IL6 protein, human; C117307:KRAS protein, human; C494086:STAT3 protein, human; C545373:ponatinib; C540383:ruxolitinib; C512478:EGFR protein, human; C507904:JAK1 protein, human