title: Targeted inhibition of the molecular chaperone Hsp90 overcomes ALK inhibitor resistance in non-small cell lung cancer.
abstract: EML4-ALK gene rearrangements define a unique subset of patients with non-small cell lung carcinoma (NSCLC), and the clinical success of the anaplastic lymphoma kinase (ALK) inhibitor crizotinib in this population has become a paradigm for molecularly targeted therapy. Here, we show that the Hsp90 inhibitor ganetespib induced loss of EML4-ALK expression and depletion of multiple oncogenic signaling proteins in ALK-driven NSCLC cells, leading to greater in vitro potency, superior antitumor efficacy, and prolonged animal survival compared with results obtained with crizotinib. In addition, combinatorial benefit was seen when ganetespib was used with other targeted ALK agents both in vitro and in vivo. Importantly, ganetespib overcame multiple forms of crizotinib resistance, including secondary ALK mutations, consistent with activity seen in a patient with crizotinib-resistant NSCLC. Cancer cells driven by ALK amplification and oncogenic rearrangements of ROS1 and RET kinase genes were also sensitive to ganetespib exposure. Taken together, these results highlight the therapeutic potential of ganetespib for ALK-driven NSCLC.
  
  
  CONCLUSIONS
  In addition to direct kinase inhibition, pharmacologic blockade of the molecular chaperone Hsp90 is emerging as a promising approach for treating tumors driven by oncogenic rearrangements of ALK. The bioactivity profi le of ganetespib presented here underscores a new therapeutic opportunity to target ALK and overcome multiple mechanisms of resistance in patients with ALK-positive NSCLC.
authors.affiliation: Synta Pharmaceuticals Corp, Lexington, MA 02421, USA.
authors.forename: Jim
authors.initials: J
authors.lastname: Sang
authors.forename: Jaime
authors.initials: J
authors.lastname: Acquaviva
authors.forename: Julie C
authors.initials: JC
authors.lastname: Friedland
authors.forename: Donald L
authors.initials: DL
authors.lastname: Smith
authors.forename: Manuel
authors.initials: M
authors.lastname: Sequeira
authors.forename: Chaohua
authors.initials: C
authors.lastname: Zhang
authors.forename: Qin
authors.initials: Q
authors.lastname: Jiang
authors.forename: Liquan
authors.initials: L
authors.lastname: Xue
authors.forename: Christine M
authors.initials: CM
authors.lastname: Lovly
authors.forename: John-Paul
authors.initials: JP
authors.lastname: Jimenez
authors.forename: Alice T
authors.initials: AT
authors.lastname: Shaw
authors.forename: Robert C
authors.initials: RC
authors.lastname: Doebele
authors.forename: Suqin
authors.initials: S
authors.lastname: He
authors.forename: Richard C
authors.initials: RC
authors.lastname: Bates
authors.forename: D Ross
authors.initials: DR
authors.lastname: Camidge
authors.forename: Stephan W
authors.initials: SW
authors.lastname: Morris
authors.forename: Iman
authors.initials: I
authors.lastname: El-Hariry
authors.forename: David A
authors.initials: DA
authors.lastname: Proia
mesh_terms: D000328:Adult; D000077548:Anaplastic Lymphoma Kinase; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D000077547:Crizotinib; D019008:Drug Resistance, Neoplasm; D005260:Female; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D008297:Male; D051379:Mice; D008819:Mice, Nude; D016513:Mice, SCID; D011720:Pyrazoles / Q000008:administration & dosage; D011725:Pyridines / Q000008:administration & dosage; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics*; D014230:Triazoles / Q000008:administration & dosage*; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D018841:HSP90 Heat-Shock Proteins; D011720:Pyrazoles; D011725:Pyridines; C533237:STA 9090; D014230:Triazoles; D000077547:Crizotinib; C000626173:ALK protein, human; C000626174:Alk protein, mouse; D000077548:Anaplastic Lymphoma Kinase; D020794:Receptor Protein-Tyrosine Kinases