EGFR Exon 20 Insertion Mutations Display Sensitivity to Hsp90 Inhibition in Preclinical Models and Lung Adenocarcinomas

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
Susan E JorgeDaniel B Costa

Abstract

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. 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. 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. 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 pur...Continue Reading

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Citations

Jun 26, 2020·Expert Review of Anticancer Therapy·Kamya SankarAngel Qin
Sep 22, 2020·Expert Opinion on Drug Delivery·Archana UpadhyaAmbikanandan Misra
Jun 9, 2020·Frontiers in Pharmacology·Wenqiang CuiShuguang Yuan
Apr 3, 2020·Expert Review of Respiratory Medicine·Simona Scodes, Federico Cappuzzo
May 4, 2020·Journal of Cancer Research and Clinical Oncology·Yue ZhaoHaiquan Chen
Mar 12, 2019·Signal Transduction and Targeted Therapy·Simon Vyse, Paul H Huang
Jun 12, 2019·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Anna TruiniKaterina Politi
May 3, 2020·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Susan E JorgeDaniel B Costa
Sep 27, 2020·Cancer Treatment Reviews·Jordi RemonBenjamin Besse
Mar 18, 2021·Pharmacogenomics and Personalized Medicine·Laura PaciniPaul H Huang
Oct 24, 2018·Annals of Oncology : Official Journal of the European Society for Medical Oncology·Z PiotrowskaL V Sequist
Jul 29, 2021·ELife·Ioannis GaldadasFrancesco Luigi Gervasio
Sep 26, 2021·Nature Reviews. Clinical Oncology·Alex FriedlaenderAlfredo Addeo

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