Acquired resistance to IDH inhibition through trans or cis dimer-interface mutations.
Acquired resistance to IDH inhibition through trans or cis dimer-interface mutations.
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DOI：
10.1038/s41586-018-0251-7
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发表时间：
2018-07
期刊：
影响因子：
64.8
通讯作者：
Stein EM
中科院分区：
文献类型：
--
作者：
Intlekofer AM;Shih AH;Wang B;Nazir A;Rustenburg AS;Albanese SK;Patel M;Famulare C;Correa FM;Takemoto N;Durani V;Liu H;Taylor J;Farnoud N;Papaemmanuil E;Cross JR;Tallman MS;Arcila ME;Roshal M;Petsko GA;Wu B;Choe S;Konteatis ZD;Biller SA;Chodera JD;Thompson CB;Levine RL;Stein EM
异柠檬酸脱氢酶 2 (IDH2) 的体细胞突变通过产生致癌代谢物 2-羟基戊二酸 (2HG) 促进急性髓系白血病 (AML) 的发病。 Enasidenib (AG-221) 是一种变构抑制剂，可与 IDH2 二聚体界面结合并阻断 IDH2 突变体产生 2HG。在 I/II 期临床试验中，enasidenib 抑制 2HG 产生并诱导复发/难治性 IDH2 突变 AML 的临床反应。在这里，我们描述了两名 IDH2 突变 AML 患者，他们对enasidenib 有临床反应，随后出现临床耐药、疾病进展和循环 2HG 反复升高。我们发现治疗耐药性与反式第二位点 IDH2 突变的出现有关，例如，耐药性突变发生在 IDH2 等位基因中，而没有新形态的 R140Q 突变。反式突变发生在谷氨酰胺 316 (Q316E) 和异亮氨酸 319 (I319M) 处，它们位于enasidenib 与 IDH2 二聚体结合的界面处。这些突变疾病等位基因的单独表达不会诱导 2HG 产生，但是 Q316E 和 I319M 突变的表达与反式 IDH2 R140Q 一致，允许产生 2HG，且对enasidenib 的抑制具有抗性。生化研究预测，对变构 IDH 抑制剂的耐药性也可能通过顺式 IDH 二聚体界面突变而发生，这一点在一名对 IDH1 抑制剂 ivosidenib (AG-120) 获得性耐药的患者中得到证实。我们的观察阐明了一种对靶向治疗获得性耐药的新机制，并强调了 2HG 产生对 IDH 突变恶性肿瘤发病机制的重要性。
Somatic mutations in isocitrate dehydrogenase 2 (IDH2) contribute to the pathogenesis of acute myeloid leukemia (AML) through production of the oncometabolite 2-hydroxyglutarate (2HG). Enasidenib (AG-221) is an allosteric inhibitor that binds to the IDH2 dimer interface and blocks 2HG production by IDH2 mutants. In a phase I/II clinical trial, enasidenib inhibited 2HG production and induced clinical responses in relapsed/refractory IDH2-mutant AML. Here we describe two patients with IDH2-mutant AML who had a clinical response to enasidenib followed by clinical resistance, disease progression, and recurrent elevation in circulating 2HG. We found that therapeutic resistance was associated with the emergence of second-site IDH2 mutations in trans, such that resistance mutations occurred in the IDH2 allele without the neomorphic R140Q mutation. The in trans mutations occurred at glutamine 316 (Q316E) and isoleucine 319 (I319M), which are at the interface where enasidenib binds the IDH2 dimer. Expression of these mutant disease alleles alone did not induce 2HG production, however expression of Q316E and I319M mutations in concert with IDH2 R140Q in trans allowed for 2HG production that was resistant to inhibition by enasidenib. Biochemical studies predicted that resistance to allosteric IDH inhibitors could also occur via IDH dimer-interface mutations in cis, which was confirmed in a patient with acquired resistance to the IDH1 inhibitor ivosidenib (AG-120). Our observations elucidate a novel mechanism of acquired resistance to a targeted therapy and underscore the importance of 2HG production to the pathogenesis of IDH-mutant malignancies.
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影响因子：
10.5
作者：
Chen C;Liu Y;Lu C;Cross JR;Morris JP 4th;Shroff AS;Ward PS;Bradner JE;Thompson C;Lowe SW
通讯作者：
Lowe SW
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
50.3
作者：
Ward PS;Patel J;Wise DR;Abdel-Wahab O;Bennett BD;Coller HA;Cross JR;Fantin VR;Hedvat CV;Perl AE;Rabinowitz JD;Carroll M;Su SM;Sharp KA;Levine RL;Thompson CB
通讯作者：
Thompson CB
影响因子：
50.3
作者：
Figueroa ME;Abdel-Wahab O;Lu C;Ward PS;Patel J;Shih A;Li Y;Bhagwat N;Vasanthakumar A;Fernandez HF;Tallman MS;Sun Z;Wolniak K;Peeters JK;Liu W;Choe SE;Fantin VR;Paietta E;Löwenberg B;Licht JD;Godley LA;Delwel R;Valk PJ;Thompson CB;Levine RL;Melnick A
通讯作者：
Melnick A
影响因子：
2.9
作者：
Jacobson, MP;Pincus, DL;Friesner, RA
通讯作者：
Friesner, RA