MET inhibition enhances PARP inhibitor efficacy in castration-resistant prostate cancer by suppressing the ATM/ATR and PI3K/AKT pathways.
MET inhibition enhances PARP inhibitor efficacy in castration-resistant prostate cancer by suppressing the ATM/ATR and PI3K/AKT pathways.
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DOI：
10.1111/jcmm.17037
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发表时间：
2021-12
影响因子：
5.3
通讯作者：
Liu Z
中科院分区：
文献类型：
--
作者：
Zhou S;Dai Z;Wang L;Gao X;Yang L;Wang Z;Wang Q;Liu Z
高达 30% 的转移性去势抵抗性前列腺癌 (CRPC) 患者携带改变的 DNA 损伤反应基因，使得聚腺苷二磷酸核糖聚合酶 (PARP) 抑制剂能够在晚期 CRPC 中使用。原癌基因间充质-上皮转化（MET）对于肿瘤细胞的迁移、增殖和侵袭至关重要。 MET 及其配体肝细胞生长因子的异常表达与癌症治疗中的耐药性相关。在这里，我们发现MET在人CRPC组织中高表达，并以药物浓度依赖性方式在DU145和PC3细胞中过度表达，并且与PARP抑制剂的敏感性密切相关。将 PARP 抑制剂奥拉帕尼与 MET 抑制剂克唑替尼联合使用，可在体内和体外协同抑制 CRPC 细胞的生长。进一步分析MET抑制诱导药物敏感性的分子机制发现，奥拉帕尼和克唑替尼可以共同下调ATM/ATR信号通路，通过抑制磷酸肌醇3激酶/蛋白激酶B（PI3K/AKT）通路诱导细胞凋亡，增强奥拉帕尼诱导的DU145和PC3细胞的抗肿瘤作用。总之，我们证明 MET 抑制通过抑制 ATM/ATR 和 PI3K/AKT 通路来增强 CRPC 对 PARP 抑制剂的敏感性，并为 CRPC 提供一种新颖的靶向治疗方案。
Up to 30% of patients with metastatic castration‐resistant prostate cancer (CRPC) patients carry altered DNA damage response genes, enabling the use of poly adenosine diphosphate–ribose polymerase (PARP) inhibitors in advanced CRPC. The proto‐oncogene mesenchymal–epithelial transition (MET) is crucial in the migration, proliferation, and invasion of tumour cells. Aberrant expression of MET and its ligand hepatocyte growth factor is associated with drug resistance in cancer therapy. Here, we found that MET was highly expressed in human CRPC tissues and overexpressed in DU145 and PC3 cells in a drug concentration‐dependent manner and is closely related to sensitivity to PARP inhibitors. Combining the PARP inhibitor olaparib with the MET inhibitor crizotinib synergistically inhibited CRPC cell growth both in vivo and in vitro. Further analysis of the underlying molecular mechanism underlying the MET suppression‐induced drug sensitivity revealed that olaparib and crizotinib could together downregulate the ATM/ATR signaling pathway, inducing apoptosis by inhibiting the phosphoinositide 3‐kinase/protein kinase B (PI3K/AKT) pathway, enhancing the olaparib‐induced antitumour effect in DU145 and PC3 cells. In conclusion, we demonstrated that MET inhibition enhances sensitivity of CRPC to PARP inhibitors by suppressing the ATM/ATR and PI3K/AKT pathways and provides a novel, targeted therapy regimen for CRPC.
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影响因子：
82.9
作者：
Du Y;Yamaguchi H;Wei Y;Hsu JL;Wang HL;Hsu YH;Lin WC;Yu WH;Leonard PG;Lee GR 4th;Chen MK;Nakai K;Hsu MC;Chen CT;Sun Y;Wu Y;Chang WC;Huang WC;Liu CL;Chang YC;Chen CH;Park M;Jones P;Hortobagyi GN;Hung MC
通讯作者：
Hung MC
影响因子：
64.8
作者：
Ray Chaudhuri A;Callen E;Ding X;Gogola E;Duarte AA;Lee JE;Wong N;Lafarga V;Calvo JA;Panzarino NJ;John S;Day A;Crespo AV;Shen B;Starnes LM;de Ruiter JR;Daniel JA;Konstantinopoulos PA;Cortez D;Cantor SB;Fernandez-Capetillo O;Ge K;Jonkers J;Rottenberg S;Sharan SK;Nussenzweig A
通讯作者：
Nussenzweig A
影响因子：
8
作者：
Cannistraci, A.;Federici, G.;Bonci, D.
通讯作者：
Bonci, D.
影响因子：
2.1
作者：
Knudsen, BS;Gmyrek, GA;Woude, GFV
通讯作者：
Woude, GFV
影响因子：
28.2
作者：
González-Billalabeitia E;Seitzer N;Song SJ;Song MS;Patnaik A;Liu XS;Epping MT;Papa A;Hobbs RM;Chen M;Lunardi A;Ng C;Webster KA;Signoretti S;Loda M;Asara JM;Nardella C;Clohessy JG;Cantley LC;Pandolfi PP
通讯作者：
Pandolfi PP