Rationale for co-targeting IGF-1R and ALK in ALK fusion-positive lung cancer.
Rationale for co-targeting IGF-1R and ALK in ALK fusion-positive lung cancer.
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ALK酪氨酸激酶抑制剂(TKI)Crizotinib在ALK融合的肺癌患者中显示出显著的活性，但其疗效受到可变的原发反应和获得性耐药的限制。在一项耐人寻味的临床观察中，我们定义了ALK和IGF-1R抑制剂之间的治疗协同作用。这项研究是对一名对IGF-1R抗体有“特殊反应”的ALK融合+肺癌患者进行的。与IGF-1R类似，ALK融合蛋白与接头IRS-1结合，IRS-1基因敲除可增强ALK抑制剂的抗肿瘤作用。在ALK TKI耐药模型中，IGF-1R通路被激活，联合抑制ALK/IGF-1R可提高治疗效果。与这一发现一致的是，在接受克里佐替尼治疗的患者的活检样本中，IGF-1R/IRS-1水平增加。总之，这些数据支持IGF-1R/IRS-1通路在ALK TKI敏感和TKI抵抗状态中的作用，并为进一步开发ALK/IGF-1R双重抑制剂的临床提供了生物学基础。
The ALK tyrosine kinase inhibitor (TKI), crizotinib, shows significant activity in patients whose lung cancers harbor ALK fusions but its efficacy is limited by variable primary responses and acquired resistance. In work arising from the intriguing clinical observation of a patient with ALK fusion+ lung cancer who had an ‘exceptional response’ to an IGF-1R antibody, we define a therapeutic synergism between ALK and IGF-1R inhibitors. Similar to IGF-1R, ALK fusion proteins bind to the adaptor, IRS-1, and IRS-1 knockdown enhances the anti-tumor effects of ALK inhibitors. In models of ALK TKI resistance, the IGF-1R pathway is activated, and combined ALK/IGF-1R inhibition improves therapeutic efficacy. Consistent with this finding, IGF-1R/IRS-1 levels are increased in biopsy samples from patients progressing on crizotinib therapy. Collectively, these data support a role for the IGF-1R/IRS-1 pathway in both ALK TKI-sensitive and TKI-resistant states and provide biological rationale for further clinical development of dual ALK/IGF-1R inhibitors.
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DOI：
10.1126/science.1226344
发表时间：
2012-10-12
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Iyer G;Hanrahan AJ;Milowsky MI;Al-Ahmadie H;Scott SN;Janakiraman M;Pirun M;Sander C;Socci ND;Ostrovnaya I;Viale A;Heguy A;Peng L;Chan TA;Bochner B;Bajorin DF;Berger MF;Taylor BS;Solit DB
通讯作者：
Solit DB
影响因子：
17.1
作者：
Chmielecki J;Foo J;Oxnard GR;Hutchinson K;Ohashi K;Somwar R;Wang L;Amato KR;Arcila M;Sos ML;Socci ND;Viale A;de Stanchina E;Ginsberg MS;Thomas RK;Kris MG;Inoue A;Ladanyi M;Miller VA;Michor F;Pao W
通讯作者：
Pao W
DOI：
10.1158/1078-0432.ccr-12-0838
发表时间：
2012-12-15
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Suehara Y;Arcila M;Wang L;Hasanovic A;Ang D;Ito T;Kimura Y;Drilon A;Guha U;Rusch V;Kris MG;Zakowski MF;Rizvi N;Khanin R;Ladanyi M
通讯作者：
Ladanyi M
影响因子：
4.6
作者：
Vazquez-Martin, Alejandro;Cufi, Silvia;Oliveras-Ferraros, Cristina;Zenobia Torres-Garcia, Violeta;Corominas-Faja, Bruna;Cuyas, Elisabet;Bonavia, Rosa;Visa, Joana;Martin-Castillo, Begona;Barrajon-Catalan, Enrique;Micol, Vicente;Bosch-Barrera, Joaquim;Menendez, Javier A.
通讯作者：
Menendez, Javier A.
影响因子：
45.3
作者：
Shaw, Alice T.;Yeap, Beow Y.;Iafrate, A. John
通讯作者：
Iafrate, A. John