Landscape of Acquired Resistance to Osimertinib in EGFR-Mutant NSCLC and Clinical Validation of Combined EGFR and RET Inhibition with Osimertinib and BLU-667 for Acquired RET Fusion.
Landscape of Acquired Resistance to Osimertinib in EGFR-Mutant NSCLC and Clinical Validation of Combined EGFR and RET Inhibition with Osimertinib and BLU-667 for Acquired RET Fusion.
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DOI：
10.1158/2159-8290.cd-18-1022
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发表时间：
2018-12
期刊：
影响因子：
28.2
通讯作者：
Sequist LV
中科院分区：
文献类型：
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作者：
Piotrowska Z;Isozaki H;Lennerz JK;Gainor JF;Lennes IT;Zhu VW;Marcoux N;Banwait MK;Digumarthy SR;Su W;Yoda S;Riley AK;Nangia V;Lin JJ;Nagy RJ;Lanman RB;Dias-Santagata D;Mino-Kenudson M;Iafrate AJ;Heist RS;Shaw AT;Evans EK;Clifford C;Ou SI;Wolf B;Hata AN;Sequist LV
我们提出了一个队列的41例奥希替尼耐药活检，其中包括两个获得性CCDC 6-RET融合。虽然RET融合已在耐药EGFR突变型NSCLC中鉴定，但其在EGFR抑制剂获得性耐药中的作用尚未得到充分描述。为了评估RET融合在EGFR突变型癌症中的生物学意义，我们在PC 9（EGFR del 19）和MGH 134（EGFR L 858 R/T790 M）细胞中表达CCDC 6-RET，发现CCDC 6-RET足以赋予对EGFR-TKI的抗性。选择性RET抑制剂BLU-667或卡博替尼使表达CCDC 6-RET的细胞对EGFR抑制重新敏感。最后，我们用奥希替尼和BLU-667治疗了2例EGFR突变型NSCLC和RET介导的耐药患者。该组合耐受性良好，并导致两名患者的快速放射学反应。本研究提供了概念验证，即RET融合可介导对EGFR TKI的获得性耐药性，并且联合使用奥希替尼/BLU-667抑制EGFR和RET可能是此类患者耐受性良好且有效的治疗策略。
We present a cohort of 41 patients with osimertinib resistance biopsies, including two with an acquired CCDC6-RET fusion. While RET fusions have been identified in resistant EGFR-mutant NSCLC, their role in acquired resistance to EGFR inhibitors is not well described. To assess the biological implications of RET fusions in an EGFR-mutant cancer, we expressed CCDC6-RET in PC9 (EGFR del19) and MGH134 (EGFR L858R/T790M) cells and found that CCDC6-RET was sufficient to confer resistance to EGFR-TKIs. The selective RET inhibitors BLU-667 or cabozantinib resensitized CCDC6-RET-expressing cells to EGFR inhibition. Finally, we treated two patients with EGFR-mutant NSCLC and RET-mediated resistance with osimertinib and BLU-667. The combination was well-tolerated and led to rapid radiographic response in both patients. This study provides proof-of-concept that RET fusions can mediate acquired resistance to EGFR TKIs and that combined EGFR and RET inhibition with osimertinib/BLU-667 may be a well-tolerated and effective treatment strategy for such patients.