Heterogeneous responses and resistant mechanisms to crizotinib in ALK-positive advanced non-small cell lung cancer.
Heterogeneous responses and resistant mechanisms to crizotinib in ALK-positive advanced non-small cell lung cancer.
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DOI：
10.1111/1759-7714.12791
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发表时间：
2018-09
期刊：
影响因子：
2.9
通讯作者：
Yang JJ
中科院分区：
文献类型：
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作者：
Kang J;Chen HJ;Zhang XC;Su J;Zhou Q;Tu HY;Wang Z;Wang BC;Zhong WZ;Yang XN;Chen ZH;Ding Y;Wu X;Wang M;Fu JG;Yang Z;Zhang X;Shao YW;Wu YL;Yang JJ
ALK酪氨酸激酶抑制剂（TKI）已被证明可有效治疗ALK阳性非小细胞肺癌（NSCLC），尽管患者的缓解和疾病进展过程各不相同。详细的潜在分子机制需要进一步研究，以获得更好的预后。对42例经荧光原位杂交或免疫组织化学证实为ALK重排阳性的克唑替尼治疗后发生疾病进展的NSCLC患者的样本进行了靶向下一代测序（NGS）突变分析。 在6例（14%）NGS确定的其他潜在致癌驱动因素患者中未证实ALK重排，因此与NGS ALK阳性患者相比，这些患者对克唑替尼无应答，总生存期（OS）显著缩短。在8/26份治疗后样本（31%）中检测到15种ALK激活突变，其中ALK L1196 M和G1269 A是半数ALK激活突变患者中检测到的最常见获得性突变。动态监测1例患者的遗传进化，发现不同ALK‐TKI疗程期间耐药机制的空间和时间异质性。在没有ALK激活突变的患者中检测到ALK下游或旁路途径的激活，例如PIK 3CA、MET和KRAS的遗传变异。有趣的是，我们发现了两名患者的DNA错配修复基因POLE发生了获得性突变，这导致肿瘤突变负荷显著增加，并可能导致克唑替尼的疗效差。已经确定了异质性耐药机制，并与克唑替尼的不同反应相关。为了更好地预测临床结果，需要进行全面和动态的突变分析。
ALK‐tyrosine kinase inhibitors (TKIs) have been proven effective for treating ALK‐positive non‐small cell lung cancer (NSCLC), although patients present with variable responses and disease progression courses. The detailed underlying molecular mechanisms require further investigation to yield a better prognosis. Targeted next‐generation sequencing (NGS) mutation profiling was performed on samples from 42 NSCLC patients confirmed positive for ALK rearrangements by fluorescence in situ hybridization or immunohistochemistry who experienced disease progression after crizotinib treatment. ALK rearrangements were not confirmed in six patients (14%) with other potential oncogenic drivers identified by NGS, who therefore did not respond to crizotinib and had significantly shorter overall survival (OS) compared to NGS ALK ‐positive patients. Fifteen ALK activating mutations were detected in 8 out of 26 post‐treatment samples (31%), among which ALK L1196M and G1269A were the most common acquired mutations detected in half of the patients with ALK activating mutations. Dynamic monitoring of the genetic evolution in one patient revealed both spatial and temporal heterogeneity of resistant mechanisms during different ALK‐TKI treatment courses. Activation of ALK downstream or bypass pathways was detected in patients without ALK activating mutations, such as genetic alterations in PIK3CA, MET, and KRAS. Interestingly, we identified two patients with acquired mutations in the DNA mismatch repair gene POLE, which resulted in a dramatically increased tumor mutation burden, and might contribute to the poor response to crizotinib. Heterogeneous resistant mechanisms have been identified and correlate to diverse responses to crizotinib. Comprehensive and dynamic mutation profiling is required to better predict clinical outcomes.
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影响因子：
8.4
作者：
Eisenhauer, E. A.;Therasse, P.;Verweij, J.
通讯作者：
Verweij, J.
影响因子：
28.2
作者：
Friboulet L;Li N;Katayama R;Lee CC;Gainor JF;Crystal AS;Michellys PY;Awad MM;Yanagitani N;Kim S;Pferdekamper AC;Li J;Kasibhatla S;Sun F;Sun X;Hua S;McNamara P;Mahmood S;Lockerman EL;Fujita N;Nishio M;Harris JL;Shaw AT;Engelman JA
通讯作者：
Engelman JA
DOI：
10.1200/jco.2017.76.2294
发表时间：
2018-04-20
期刊：
Journal of clinical oncology : official journal of the American Society of Clinical Oncology
影响因子：
--
作者：
Lin JJ;Zhu VW;Yoda S;Yeap BY;Schrock AB;Dagogo-Jack I;Jessop NA;Jiang GY;Le LP;Gowen K;Stephens PJ;Ross JS;Ali SM;Miller VA;Johnson ML;Lovly CM;Hata AN;Gainor JF;Iafrate AJ;Shaw AT;Ou SI
通讯作者：
Ou SI
影响因子：
50.3
作者：
Zou HY;Friboulet L;Kodack DP;Engstrom LD;Li Q;West M;Tang RW;Wang H;Tsaparikos K;Wang J;Timofeevski S;Katayama R;Dinh DM;Lam H;Lam JL;Yamazaki S;Hu W;Patel B;Bezwada D;Frias RL;Lifshits E;Mahmood S;Gainor JF;Affolter T;Lappin PB;Gukasyan H;Lee N;Deng S;Jain RK;Johnson TW;Shaw AT;Fantin VR;Smeal T
通讯作者：
Smeal T
使用下一代 DNA 测序数据进行变异发现和基因分型的框架。
影响因子：
30.8
作者：
通讯作者：
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