STAT3 inhibition suppresses adaptive survival of ALK-rearranged lung cancer cells through transcriptional modulation of apoptosis.
STAT3 inhibition suppresses adaptive survival of ALK-rearranged lung cancer cells through transcriptional modulation of apoptosis.
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DOI：
10.1038/s41698-022-00254-y
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发表时间：
2022-02-28
影响因子：
7.9
通讯作者：
Yano S
中科院分区：
文献类型：
--
作者：
Yanagimura N;Takeuchi S;Fukuda K;Arai S;Tanimoto A;Nishiyama A;Ogo N;Takahashi H;Asai A;Watanabe S;Kikuchi T;Yano S
晚期间变性淋巴瘤激酶(ALK)重排的非小细胞肺癌患者在服用ALK酪氨酸激酶抑制剂(ALK-TKI)后很少有完全缓解，残留的肿瘤复发为异质性耐药表型。在此，我们研究了新的治疗策略，以减少和消除早期治疗阶段的残留肿瘤。利用小引导RNA文库进行的功能基因组筛选表明，ALK重排的肺癌细胞在治疗后的适应性存活主要依赖于ALK抑制下的STAT3活性。STAT3抑制通过增强ALK抑制诱导的细胞凋亡，有效地抑制ALK重排肺癌细胞的适应性存活。联合作用的特点是治疗诱导的STAT3依赖和抗凋亡因子bclxl的转录调节。在异种移植研究中，与单独使用阿莱替尼相比，联合使用YHO-1701(STAT3抑制剂)和阿莱替尼显著抑制了停止治疗并接近肿瘤缓解后的肿瘤再生长。因此，这项研究为ALK重排肺癌患者的联合治疗策略提供了新的见解。
Patients with advanced anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer who are prescribed ALK-tyrosine kinase inhibitors (ALK-TKIs) rarely have complete responses, with residual tumors relapsing as heterogeneous resistant phenotypes. Herein, we investigated new therapeutic strategies to reduce and eliminate residual tumors in the early treatment phase. Functional genomic screening using small guide RNA libraries showed that treatment-induced adaptive survival of ALK-rearranged lung cancer cells was predominantly dependent on STAT3 activity upon ALK inhibition. STAT3 inhibition effectively suppressed the adaptive survival of ALK-rearranged lung cancer cells by enhancing ALK inhibition-induced apoptosis. The combined effects were characterized by treatment-induced STAT3 dependence and transcriptional regulation of anti-apoptotic factor BCL-XL. In xenograft study, the combination of YHO-1701 (STAT3 inhibitor) and alectinib significantly suppressed tumor regrowth after treatment cessation with near tumor remission compared with alectinib alone. Hence, this study provides new insights into combined therapeutic strategies for patients with ALK-rearranged lung cancer.
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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：
82.9
作者：
Bivona TG;Doebele RC
通讯作者：
Doebele RC
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：
10.1158/1078-0432.ccr-14-1511
发表时间：
2014-11-15
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Katayama R;Friboulet L;Koike S;Lockerman EL;Khan TM;Gainor JF;Iafrate AJ;Takeuchi K;Taiji M;Okuno Y;Fujita N;Engelman JA;Shaw AT
通讯作者：
Shaw AT
影响因子：
3.5
作者：
GERBER, PR;MULLER, K
通讯作者：
MULLER, K