Acquired Resistance to the Hsp90 Inhibitor, Ganetespib, inKRAS-Mutant NSCLC Is Mediated via Reactivation of the ERK-p90RSK-mTOR Signaling Network.
Approximately 25% of non-small cell lung cancer (NSCLC) patients haveKRASmutations, and no effective therapeutic strategy exists for these patients. The use of Hsp90 inhibitors inKRAS-mutant NSCLC appeared to be a promising approach, as these inhibitors target many KRAS downstream effectors; however, limited clinical efficacy has been observed due to resistance. Here, we examined the mechanism(s) of acquired resistance to the Hsp90 inhibitor, ganetespib, and identified novel and rationally devised Hsp90 inhibitor combinations, which may prevent and overcome resistance to Hsp90 inhibitors. We derivedKRAS-mutant NSCLC ganetespib-resistant cell lines to identify the resistance mechanism(s) and identified hyperactivation of RAF/MEK/ERK/RSK and PI3K/AKT/mTOR pathways as key resistance mechanisms. Furthermore, we found that ganetespib-resistant cells are "addicted" to these pathways, as ganetespib resistance leads to synthetic lethality to a dual PI3K/mTOR, a PI3K, or an ERK inhibitor. Interestingly, the levels and activity of a key activator of the mTOR pathway and an ERK downstream target, p90 ribosomal S6 kinase (RSK), were also increased in the ganetespib-resistant cells. Genetic or pharmacologic inhibition of p90RSK in ganetespib-resistant cells restored sensitivity to ganetespib, whereas p90RSK overexpression induced ganetespib resistance in naïve cells, validating p90RSK as a mediator of resistance and a novel therapeutic target. Our studies offer a way forward for Hsp90 inhibitors through the rational design of Hsp90 inhibitor combinations that may prevent and/or overcome resistance to Hsp90 inhibitors, providing an effective therapeutic strategy forKRAS-mutant NSCLC.Mol Cancer Ther; 16(5); 793-804. ©2017 AACR.
Department of Medicine, Division of Hematology Oncology, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania.
Suman
S
Chatterjee
Department of Medicine, Division of Hematology Oncology, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania.
Eric H-B
EH
Huang
Department of Medicine, Division of Hematology Oncology, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania.
Ian
I
Christie
Department of Biostatistics, University of Pittsburgh, Pittsburgh, Pennsylvania.
Brenda F
BF
Kurland
Department of Medicine, Division of Hematology Oncology, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania. burnstf@upmc.edu.
Timothy F
TF
Burns
D000072283:A549 Cells; D000818:Animals; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D018841:HSP90 Heat-Shock Proteins / Q000235:genetics; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D051379:Mice; D009154:Mutation; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000235:genetics*; D058570:TOR Serine-Threonine Kinases / Q000235:genetics; D014230:Triazoles / Q000008:administration & dosage; D023041:Xenograft Model Antitumor Assays
D018841:HSP90 Heat-Shock Proteins; C117307:KRAS protein, human; D047428:Protein Kinase Inhibitors; C533237:STA 9090; D014230:Triazoles; C546842:MTOR protein, human; D038744:Ribosomal Protein S6 Kinases, 90-kDa; D058570:TOR Serine-Threonine Kinases; D016283:Proto-Oncogene Proteins p21(ras)