Abstract 4752: Exon-16-skipping HER2 contributes to osimertinib-resistance through Src-independent manner inEGFRL858R/T790M-positive non-small-cell lung cancer

Osimertinib is current recommended treatment for EGFR T790M-positive NSCLC following progression on prior EGFR tyrosine kinase inhibitor therapy. However, acquired resistance to osimertinib therapy inevitably developed after a period of effective treatment. We had a patient of EGFR L858R/T790M-positive NSCLC who initially responded to osimertinib therapy but eventually developed resistance. Plasma cell-free DNA analysis disclosed exon-16-skipping HER2 (HER2Δ16) in one osimertinib treated patient. HER2Δ16 was regarded as an oncogenic driver in breast cancer and has never been reported in lung cancer before. Therefore, it’s intriguing to investigate the role of HER2Δ16 in osimertinib resistance in NSCLC. The purpose of this study is to explore the mechanism of HER2Δ16-mediated resistance to osimertinib and to explore strategies to overcome the resistance. We constructed and established H1975 cells stably expressing either vehicle, WT-HER2 or HER2Δ16. We observed that without osimertinib treatment, there was no difference in cell growth and the response to EGF-stimulation. However, when treated with osimertinib, H1975-HER2Δ16 cells were more resistant under normal and EGF-stimulating conditions compared to vehicle or WT-HER2 expressing cells. Moreover, osimertinib treatment in H1975-HER2Δ16 cells had less inhibitory effect on phosphor-ERK and phosphor-AKT compared to vehicle or H1975-WT-HER2 cells. Interestingly, co-treatment of osimertinib with Src-kinase inhibitor, dasatinib, failed to reverse the resistance, indicating that HER2Δ16-driven osimertinib-resistance was independent of Src-kinase. Finally, we revealed that combination of osimertinib with the HER2 small molecular inhibitor, afatinib, can suppress cell growth in H1975-WT-HER2 and H1975-HER2Δ16 cells. In summary, we have shown that HER2Δ16, may be a resistance mechanism to osimertinib in EGFR mutated NSCLC and that HER2Δ16-driven resistance was Src-kinase independent. Moreover, we found the HER2Δ16-driven resistance could be rescued by combination of osimertinib with afatinib. Citation Format: Chia-Chi Hsu, Bin-Chi Liao, Wei-Yu Liao, Aleksandra Markovets, Daniel Stetson, Kenneth Thress, Chih-Hsin Yang. Exon-16-skipping HER2 contributes to osimertinib-resistance through Src-independent manner in EGFRL858R/T790M-positive non-small-cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4752.