Lorlatinib and capmatinib in a ROS1-rearranged NSCLC with MET-driven resistance: tumor response and evolution.
Lorlatinib and capmatinib in a ROS1-rearranged NSCLC with MET-driven resistance: tumor response and evolution.
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DOI：
10.1038/s41698-023-00464-y
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发表时间：
2023-11-03
影响因子：
7.9
通讯作者：
中科院分区：
文献类型：
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作者：
获得性耐药性仍然是癌基因成瘾癌症的主要问题。阐明耐药机制可以为复发的患者提供合理的靶向治疗策略，同时为肿瘤的演变提供洞察力。在这里，我们报告了在用ROS1抑制剂序贯治疗后，获得的MET扩增是ROS1重排肺腺癌的耐药驱动因素。随后联合应用氯拉替尼和卡马替尼(一种甲硫咪唑选择性抑制剂)可诱导颅内外肿瘤反应。在复发时，对耐药肿瘤的测序显示MET D1246N突变和MET扩增丢失。我们对一系列肿瘤和血浆样本进行了综合分子分析，揭示了ROS1融合驱动器和MET旁路轴在基因组和蛋白质水平的动态变化以及多克隆耐药的出现。这一案例说明了序贯靶向治疗纵向肿瘤进化的复杂性，突出了当前精确肿瘤学范例中蕴含的挑战，以及开发防止耐药性的方法的重要性。
Acquired drug resistance remains a major problem across oncogene-addicted cancers. Elucidation of mechanisms of resistance can inform rational treatment strategies for patients relapsing on targeted therapies while offering insights into tumor evolution. Here, we report acquired MET amplification as a resistance driver in a ROS1-rearranged lung adenocarcinoma after sequential treatment with ROS1 inhibitors. Subsequent combination therapy with lorlatinib plus capmatinib, a MET-selective inhibitor, induced intracranial and extracranial tumor response. At relapse, sequencing of the resistant tumor revealed a MET D1246N mutation and loss of MET amplification. We performed integrated molecular analyses of serial tumor and plasma samples, unveiling dynamic alterations in the ROS1 fusion driver and MET bypass axis at genomic and protein levels and the emergence of polyclonal resistance. This case illustrates the complexity of longitudinal tumor evolution with sequential targeted therapies, highlighting challenges embedded in the current precision oncology paradigm and the importance of developing approaches that prevent resistance.
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影响因子：
28.2
作者：
Recondo G;Che J;Jänne PA;Awad MM
通讯作者：
Awad MM
影响因子：
28.2
作者：
通讯作者：
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DOI：
10.1056/nejmoa2004407
发表时间：
2020-09-03
期刊：
The New England journal of medicine
影响因子：
--
作者：
Paik PK;Felip E;Veillon R;Sakai H;Cortot AB;Garassino MC;Mazieres J;Viteri S;Senellart H;Van Meerbeeck J;Raskin J;Reinmuth N;Conte P;Kowalski D;Cho BC;Patel JD;Horn L;Griesinger F;Han JY;Kim YC;Chang GC;Tsai CL;Yang JC;Chen YM;Smit EF;van der Wekken AJ;Kato T;Juraeva D;Stroh C;Bruns R;Straub J;Johne A;Scheele J;Heymach JV;Le X
通讯作者：
Le X
影响因子：
--
作者：
Drilon, Alexander;Chiu, Chao-Hua;Fan, Yun;Cho, Byoung Chul;Lu, Shun;Ahn, Myung-Ju;Krebs, Matthew G.;Liu, Stephen, V;John, Thomas;Otterson, Gregory A.;Tan, Daniel S. W.;Patil, Tejas;Dziadziuszko, Rafal;Massarelli, Erminia;Seto, Takashi;Doebele, Robert C.;Pitcher, Bethany;Kurtsikidze, Nino;Heinzmann, Sebastian;Siena, Salvatore
通讯作者：
Siena, Salvatore
DOI：
10.1158/1078-0432.ccr-14-1385
发表时间：
2015-01-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Katayama R;Kobayashi Y;Friboulet L;Lockerman EL;Koike S;Shaw AT;Engelman JA;Fujita N
通讯作者：
Fujita N