EGFR exon 20 insertion mutations display sensitivity to HSP90 inhibition in preclinical models and lung adenocarcinomas

Susan E. Jorge, Antonio R. Lucena-Araujo, Hiroyuki Yasuda, Zofia Piotrowska, Geoffrey R. Oxnard, Deepa Rangachari, Mark S. Huberman, Lecia V. Sequist, Susumu S. Kobayashi, Daniel B. Costa

研究成果: Article査読

19 被引用数 (Scopus)

抄録

Purpose: EGFR exon 20 insertions account for up to 10% of all EGFR mutations in lung adenocarcinomas, representing the third most common cluster of mutations. The management of advanced cancers with these mutations remains elusive, without an approved inhibitor. Experimental Design: Preclinical models of a representative set of EGFR exon 20 insertion mutations to evaluate the efficacy of different inhibitors and description of the clinical outcome of an advanced lung cancer. Results: We show that select first-, second-, and third-generation EGFR inhibitors are unable to deter common EGFR exon 20 insertion mutants in concentrations that spare the wild-type kinase. Nonetheless, EGFR exon 20 insertion mutants associate with the Hsp90 chaperone system. We exploit this vulnerability to show that the nongeldanamycin Hsp90 inhibitor luminespib (formerly AUY922) degrades EGFR exon 20 mutations, downstream targets, and induces apoptosis. In addition, a patient whose EGFR inhibitor–insensitive lung adenocarcinoma harbored an EGFR exon 20 insertion mutation had a confirmed radiographic response to luminespib. Conclusions: The report confirms that EGFR exon 20 mutations are dependent on Hsp90 and are readily inhibited by the Hsp90 inhibitor luminespib; a treatment strategy that has been pursued in a confirmatory clinical trial (NCT01854034) for this group of lung adenocarcinomas that currently represent an unmet clinical need in precision oncology.

本文言語English
ページ(範囲)6548-6555
ページ数8
ジャーナルClinical Cancer Research
24
24
DOI
出版ステータスPublished - 2018 12 15
外部発表はい

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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