title: Hsp90 inhibition suppresses mutant EGFR-T790M signaling and overcomes kinase inhibitor resistance.
abstract: The epidermal growth factor receptor (EGFR) secondary kinase domain T790M non-small cell lung cancer (NSCLC) mutation enhances receptor catalytic activity and confers resistance to the reversible tyrosine kinase inhibitors gefitinib and erlotinib. Currently, irreversible inhibitors represent the primary approach in clinical use to circumvent resistance. We show that higher concentrations of the irreversible EGFR inhibitor CL-387,785 are required to inhibit EGFR phosphorylation in T790M-expressing cells compared with EGFR mutant NSCLC cells without T790M. Additionally, CL-387,785 does not fully suppress phosphorylation of other activated receptor tyrosine kinases (RTK) in T790M-expressing cells. These deficiencies result in residual Akt and mammalian target of rapamycin (mTOR) activities. Full suppression of EGFR-mediated signaling in T790M-expressing cells requires the combination of CL-387,785 and rapamycin. In contrast, Hsp90 inhibition overcomes these limitations in vitro and depletes cells of EGFR, other RTKs, and phospho-Akt and inhibits mTOR signaling whether or not T790M is present. EGFR-T790M-expressing cells rendered resistant to CL-387,785 by a kinase switch mechanism retain sensitivity to Hsp90 inhibition. Finally, Hsp90 inhibition causes regression in murine lung adenocarcinomas driven by mutant EGFR (L858R) with or without T790M. However, efficacy in the L858R-T790M model requires a more intense treatment schedule and responses were transient. Nonetheless, these findings suggest that Hsp90 inhibitors may be effective in T790M-expressing cells and offer an alternative therapeutic strategy for this subset of lung cancers.
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Shimamura
authors.forename: Danan
authors.initials: D
authors.lastname: Li
authors.forename: Hongbin
authors.initials: H
authors.lastname: Ji
authors.forename: Henry J
authors.initials: HJ
authors.lastname: Haringsma
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Liniker
authors.forename: Christa L
authors.initials: CL
authors.lastname: Borgman
authors.forename: April M
authors.initials: AM
authors.lastname: Lowell
authors.forename: Yuko
authors.initials: Y
authors.lastname: Minami
authors.forename: Kate
authors.initials: K
authors.lastname: McNamara
authors.forename: Samanthi A
authors.initials: SA
authors.lastname: Perera
authors.forename: Sara
authors.initials: S
authors.lastname: Zaghlul
authors.forename: Roman K
authors.initials: RK
authors.lastname: Thomas
authors.forename: Heidi
authors.initials: H
authors.lastname: Greulich
authors.forename: Susumu
authors.initials: S
authors.lastname: Kobayashi
authors.forename: Lucian R
authors.initials: LR
authors.lastname: Chirieac
authors.forename: Robert F
authors.initials: RF
authors.lastname: Padera
authors.forename: Shigeto
authors.initials: S
authors.lastname: Kubo
authors.forename: Masaya
authors.initials: M
authors.lastname: Takahashi
authors.forename: Daniel G
authors.initials: DG
authors.lastname: Tenen
authors.forename: Matthew
authors.initials: M
authors.lastname: Meyerson
authors.forename: Kwok-Kin
authors.initials: KK
authors.lastname: Wong
authors.forename: Geoffrey I
authors.initials: GI
authors.lastname: Shapiro
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000473:pathology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D066246:ErbB Receptors / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism*; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D009154:Mutation; D011494:Protein Kinases / Q000378:metabolism; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D018841:HSP90 Heat-Shock Proteins; D011494:Protein Kinases; C546843:mTOR protein, mouse; D066246:ErbB Receptors; D058570:TOR Serine-Threonine Kinases