Mechanisms of resistance to selective RET tyrosine kinase inhibitors in RET fusion-positive non-small-cell lung cancer.
Mechanisms of resistance to selective RET tyrosine kinase inhibitors in RET fusion-positive non-small-cell lung cancer.
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DOI：
10.1016/j.annonc.2020.09.015
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发表时间：
2020-12
期刊：
影响因子：
--
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转染期间重排（RET）基因融合是非小细胞肺癌（NSCLC）中的经验证的靶标。RET选择性抑制剂selpercatinib（LOXO-292）和pralsetinib（BLU-667）最近在晚期RET融合阳性NSCLC中表现出良好的抗肿瘤活性和安全性特征，两者均已获得美国食品药品监督管理局批准用于该适应症。对选择性RET抑制剂耐药机制的了解仍然有限。这项研究在五个机构进行。组织和/或细胞游离DNA来自selpercatinib或pralsetinib治疗后的RET融合阳性NSCLC患者，并通过下一代测序（NGS）或MET荧光原位杂交进行评估。我们分析了来自18例接受RET选择性抑制剂治疗的RET融合阳性患者（selpercatinib，n=10; pralsetinib，n=7; pralsetinib后selpercatinib，n=1，每种抑制剂后活检）的共23例治疗后组织和/或血浆活检。3例病例有成对的组织和血浆样本，其中1例还有2份连续耐药组织样本。RET抑制剂治疗的中位无进展生存期为6.3个月[95%置信区间（CI），3.6-10.8个月]。在两例（10%）中鉴定出获得性RET突变，均影响激酶溶剂前沿的RET G810残基。3例耐药病例（15%）携带获得性MET扩增，无并发RET耐药突变，1例标本获得性KRAS扩增。NGS未发现其他典型驱动因子改变。在16个耐药肿瘤标本中，没有一个有鳞状或小细胞组织学转化的证据。RET溶剂前沿突变是RET抑制剂耐药的复发机制，尽管它们发生的频率相对较低。大多数对选择性RET抑制的耐药性可能是由RET非依赖性耐药性驱动的，如获得性MET或KRAS扩增。需要具有针对RET耐药突变效力的下一代RET抑制剂和联合策略来有效克服这些患者的耐药性。
Rearranged during transfection (RET) gene fusions are a validated target in non-small cell lung cancer (NSCLC). RET-selective inhibitors selpercatinib (LOXO-292) and pralsetinib (BLU-667) recently demonstrated favorable antitumor activity and safety profiles in advanced RET fusion-positive NSCLC, and both have received approval by the US Food and Drug Administration for this indication. Insights into mechanisms of resistance to selective RET inhibitors remain limited. This study was performed at five institutions. Tissue and/or cell-free DNA was obtained from patients with RET fusion-positive NSCLC after treatment with selpercatinib or pralsetinib and assessed by next-generation sequencing (NGS) or MET fluorescence in situ hybridization. We analyzed a total of 23 post-treatment tissue and/or plasma biopsies from 18 RET fusion-positive patients who received a RET-selective inhibitor (selpercatinib, n=10; pralsetinib, n=7; pralsetinib followed by selpercatinib, n=1 with biopsy after each inhibitor). Three cases had paired tissue and plasma samples, of which one also had two serial resistant tissue specimens. The median progression-free survival on RET inhibitors was 6.3 months [95% confidence interval (CI), 3.6–10.8 months]. Acquired RET mutations were identified in two cases (10%), both affecting the RET G810 residue in the kinase solvent front. Three resistant cases (15%) harbored acquired MET amplification without concurrent RET resistance mutations, and one specimen had acquired KRAS amplification. No other canonical driver alterations were identified by NGS. Among 16 resistant tumor specimens, none had evidence of squamous or small cell histologic transformation. RET solvent front mutations are a recurrent mechanism of RET inhibitor resistance, although they occurred at a relatively low frequency. The majority of resistance to selective RET inhibition may be driven by RET-independent resistance such as acquired MET or KRAS amplification. Next-generation RET inhibitors with potency against RET resistance mutations and combination strategies are needed to effectively overcome resistance in these patients.
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DOI：
10.1158/1078-0432.ccr-18-0876
发表时间：
2018-12-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Bahcall M;Awad MM;Sholl LM;Wilson FH;Xu M;Wang S;Palakurthi S;Choi J;Ivanova EV;Leonardi GC;Ulrich BC;Paweletz CP;Kirschmeier PT;Watanabe M;Baba H;Nishino M;Nagy RJ;Lanman RB;Capelletti M;Chambers ES;Redig AJ;VanderLaan PA;Costa DB;Imamura Y;Jänne PA
通讯作者：
Jänne PA
影响因子：
82.9
作者：
Kohno T;Ichikawa H;Totoki Y;Yasuda K;Hiramoto M;Nammo T;Sakamoto H;Tsuta K;Furuta K;Shimada Y;Iwakawa R;Ogiwara H;Oike T;Enari M;Schetter AJ;Okayama H;Haugen A;Skaug V;Chiku S;Yamanaka I;Arai Y;Watanabe S;Sekine I;Ogawa S;Harris CC;Tsuda H;Yoshida T;Yokota J;Shibata T
通讯作者：
Shibata T
影响因子：
--
作者：
Gainor JF;Gadgeel S;Ou SI;Yeap B;Otterson GA;Shaw AT
通讯作者：
Shaw AT
影响因子：
82.9
作者：
Hrustanovic G;Olivas V;Pazarentzos E;Tulpule A;Asthana S;Blakely CM;Okimoto RA;Lin L;Neel DS;Sabnis A;Flanagan J;Chan E;Varella-Garcia M;Aisner DL;Vaishnavi A;Ou SH;Collisson EA;Ichihara E;Mack PC;Lovly CM;Karachaliou N;Rosell R;Riess JW;Doebele RC;Bivona TG
通讯作者：
Bivona TG
影响因子：
51.1
作者：
Drilon, Alexander;Rekhtman, Natasha;Arcila, Maria;Wang, Lu;Ni, Andy;Albano, Melanie;Van Voorthuysen, Martine;Somwar, Romel;Smith, Roger S.;Montecalvo, Joseph;Plodkowski, Andrew;Ginsberg, Michelle S.;Riely, Gregory J.;Rudin, Charles M.;Ladanyi, Marc;Kris, Mark G.
通讯作者：
Kris, Mark G.