Abstract
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.
| Original language | English |
|---|---|
| Pages (from-to) | 6548-6555 |
| Number of pages | 8 |
| Journal | Clinical Cancer Research |
| Volume | 24 |
| Issue number | 24 |
| DOIs | |
| Publication status | Published - 2018 Dec 15 |
| Externally published | Yes |
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ASJC Scopus subject areas
- Oncology
- Cancer Research
Cite this
EGFR exon 20 insertion mutations display sensitivity to HSP90 inhibition in preclinical models and lung adenocarcinomas. / Jorge, Susan E.; Lucena-Araujo, Antonio R.; Yasuda, Hiroyuki; Piotrowska, Zofia; Oxnard, Geoffrey R.; Rangachari, Deepa; Huberman, Mark S.; Sequist, Lecia V.; Kobayashi, Susumu S.; Costa, Daniel B.
In: Clinical Cancer Research, Vol. 24, No. 24, 15.12.2018, p. 6548-6555.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - EGFR exon 20 insertion mutations display sensitivity to HSP90 inhibition in preclinical models and lung adenocarcinomas
AU - Jorge, Susan E.
AU - Lucena-Araujo, Antonio R.
AU - Yasuda, Hiroyuki
AU - Piotrowska, Zofia
AU - Oxnard, Geoffrey R.
AU - Rangachari, Deepa
AU - Huberman, Mark S.
AU - Sequist, Lecia V.
AU - Kobayashi, Susumu S.
AU - Costa, Daniel B.
PY - 2018/12/15
Y1 - 2018/12/15
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85057533591&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85057533591&partnerID=8YFLogxK
U2 - 10.1158/1078-0432.CCR-18-1541
DO - 10.1158/1078-0432.CCR-18-1541
M3 - Article
C2 - 30154228
AN - SCOPUS:85057533591
VL - 24
SP - 6548
EP - 6555
JO - Clinical Cancer Research
JF - Clinical Cancer Research
SN - 1078-0432
IS - 24
ER -