SHP2 inhibition restores sensitivity in ALK-rearranged non-small-cell lung cancer resistant to ALK inhibitors.
SHP2 inhibition restores sensitivity in ALK-rearranged non-small-cell lung cancer resistant to ALK inhibitors.
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DOI：
10.1038/nm.4497
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发表时间：
2018-05
期刊：
影响因子：
82.9
通讯作者：
Engelman JA
中科院分区：
文献类型：
--
作者：
Dardaei L;Wang HQ;Singh M;Fordjour P;Shaw KX;Yoda S;Kerr G;Yu K;Liang J;Cao Y;Chen Y;Lawrence MS;Langenbucher A;Gainor JF;Friboulet L;Dagogo-Jack I;Myers DT;Labrot E;Ruddy D;Parks M;Lee D;DiCecca RH;Moody S;Hao H;Mohseni M;LaMarche M;Williams J;Hoffmaster K;Caponigro G;Shaw AT;Hata AN;Benes CH;Li F;Engelman JA
大多数间变性淋巴瘤激酶（ALK）重排的非小细胞肺肿瘤最初对小分子ALK抑制剂有反应，但通常会产生耐药性。在肿瘤对高效的第二代ALK抑制剂产生耐药性后，大约有一半携带ALK耐药突变，而另一半则具有其他耐药机制。后者通常具有驱动抗性的几种不同酪氨酸激酶中的至少一种的活化。预计此类肿瘤不会对第三代ALK抑制剂lorlatinib产生反应，lorlatinib能够克服所有临床确定的ALK耐药突变，并且进一步的治疗选择有限。在本文中，我们在多种ALK抑制剂耐药的患者衍生细胞（PDC）中部署了1000个基因的shRNA筛选，以发现ALK抑制的致敏剂。该方法将非受体蛋白酪氨酸磷酸酶SHP 2鉴定为多种PDC中的常见靶向耐药节点。SHP 2在多种酪氨酸激酶下游提供平行的生存输入，促进对ALK抑制剂的耐药性。最近发现的小分子SHP 2抑制剂SHP 099与ALK TKI（酪氨酸激酶抑制剂）ceritinib联合使用，通过阻止代偿性RAS和ERK 1/2再激活来阻止耐药PDC的生长。这些发现表明，ALK和SHP 2联合抑制可能是由几种不同的ALK非依赖性耐药机制驱动的耐药癌症的有希望的治疗策略。
Most anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung tumours initially respond to small molecule ALK inhibitors but drug resistance often develops. After tumours develop resistance to highly potent 2nd generation ALK inhibitors, approximately half harbor ALK resistance mutations, while the other half have other mechanisms of resistance. The latter often have activation of at least one of several different tyrosine kinases driving resistance. Such tumours are not expected to respond to the 3rd generation ALK inhibitor, lorlatinib, which is able to overcome all clinically identified ALK resistance mutations and further therapeutic options are limited. Herein, we deployed an shRNA screen of 1000 genes in multiple ALK inhibitor resistant patient derived cells (PDC) to discover sensitizers to ALK inhibition. This approach identified SHP2, a non-receptor protein tyrosine phosphatase, as a common targetable resistance node in multiple PDCs. SHP2 provides a parallel survival input downstream of multiple tyrosine kinases that promote resistance to ALK inhibitors. The recently discovered small molecule SHP2 inhibitor, SHP099, in combination with the ALK TKI (tyrosine kinase inhibitor), ceritinib, halted the growth of resistant PDCs by preventing compensatory RAS and ERK1/2 reactivation. These findings suggest that combined ALK and SHP2 inhibition may be a promising therapeutic strategy for resistant cancers driven by several different ALK-independent resistance mechanisms.
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影响因子：
82.9
作者：
通讯作者：
--
影响因子：
11.2
作者：
Sasaki T;Koivunen J;Ogino A;Yanagita M;Nikiforow S;Zheng W;Lathan C;Marcoux JP;Du J;Okuda K;Capelletti M;Shimamura T;Ercan D;Stumpfova M;Xiao Y;Weremowicz S;Butaney M;Heon S;Wilner K;Christensen JG;Eck MJ;Wong KK;Lindeman N;Gray NS;Rodig SJ;Jänne PA
通讯作者：
Jänne PA
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：
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
影响因子：
4.8
作者：
Cunnick, JM;Meng, SS;Wu, J
通讯作者：
Wu, J