Details

Autor(en) / Beteiligte

• Kosaka, Takayuki
• Tanizaki, Junko
• Paranal, Raymond M
• Endoh, Hideki
• Lydon, Christine
• Capelletti, Marzia
• Repellin, Claire E
• Choi, Jihyun
• Ogino, Atsuko
• Calles, Antonio
• Ercan, Dalia
• Redig, Amanda J
• Bahcall, Magda
• Oxnard, Geoffrey R
• Eck, Michael J
• Jänne, Pasi A

Titel

Response Heterogeneity of EGFR and HER2 Exon 20 Insertions to Covalent EGFR and HER2 Inhibitors

Ist Teil von

• Cancer research (Chicago, Ill.), 2017-05, Vol.77 (10), p.2712-2721

Ort / Verlag

United States: American Association for Cancer Research, Inc

Erscheinungsjahr

2017

Quelle

Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals

Beschreibungen/Notizen

• Insertion mutations in EGFR and HER2 both occur at analogous positions in exon 20. Non-small cell lung cancer (NSCLC) patients with tumors harboring these mutations seldom achieve clinical responses to dacomitinib and afatinib, two covalent quinazoline-based inhibitors of EGFR or HER2, respectively. In this study, we investigated the effects of specific EGFR and HER2 exon 20 insertion mutations from NSCLC patients that had clinically achieved a partial response after dacomitinib treatment. We identified Gly770 as a common feature among the drug-sensitive mutations. Structural modeling suggested that this mutation may facilitate inhibitor binding to EGFR. Introduction of Gly770 into two dacomitinib-resistant EGFR exon 20 insertion mutants restored sensitivity to dacomitinib. Based on these findings, we used afatinib to treat an NSCLC patient whose tumor harbored the HER2 V777_G778insGSP mutation and achieved a durable partial response. We further identified secondary mutations in EGFR (T790M or C797S) and HER2 (C805S) that mediated acquired drug resistance in drug-sensitive EGFR or HER2 exon 20 insertion models. Overall, our findings identified a subset of EGFR and HER2 exon 20 insertion mutations that are sensitive to existing covalent quinazoline-based EGFR/HER2 inhibitors, with implications for current clinical treatment and next-generation small-molecule inhibitors. .