IGF1R upregulation confers resistance to isoform-specific inhibitors of PI3K in PIK3CA-driven ovarian cancer.
IGF1R upregulation confers resistance to isoform-specific inhibitors of PI3K in PIK3CA-driven ovarian cancer.
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DOI：
10.1038/s41419-018-1025-8
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发表时间：
2018-09-20
影响因子：
9
通讯作者：
Elkabets M
中科院分区：
文献类型：
--
作者：
Zorea J;Prasad M;Cohen L;Li N;Schefzik R;Ghosh S;Rotblat B;Brors B;Elkabets M
PIK 3CA中的基因组改变（GA）导致超过20%的卵巢癌（OC）患者中磷脂酰肌醇-4，5-二磷酸3-激酶（PI 3 K）途径的过度活化。因此，PI 3 K疗法正在对该患者亚组进行临床评价。显然，在测试PI 3 K的亚型特异性抑制剂（PI 3 Ki）的功效的临床试验中，具有稳定疾病的患者最终复发，因为肿瘤变得对治疗有抗性。因此，临床上迫切需要开发新的治疗组合以改善PIK 3CA驱动的OC患者中PI 3 Ki的疗效。在这里，我们确定了限制β-保留PI 3 Ki，Taselisib（GDC 0032）在获得对GDC 0032的抗性的PIK 3CA突变的OC细胞系（IGROV 1和OAW 42）中的功效的分子机制。通过比较GDC 0032敏感和耐药OC细胞系的分子谱，我们发现AKT/mTOR抑制是GDC 0032功效所需的。在耐药细胞中，AKT/mTOR的持续激活受到胰岛素生长因子1受体（IGF 1 R）上调的调节。IGF 1 R的敲低在体外使细胞对GDC 0032重新致敏，并且IGF 1 R抑制剂AEW 541与GDC 0032的组合在体外和体内表现出有效的抗肿瘤活性。我们进一步证明IGF 1 R调节IGROV 1细胞中的肿瘤细胞增殖，而在OAW 42中，它也决定自噬。总体而言，我们的研究结果表明，PI 3 K和IGF 1 R的双重抑制可能被认为是PIK 3CA驱动的OC的新治疗策略。
Genomic alterations (GA) in PIK3CA leads to the hyper-activation of the phosphatidylinositol-4, 5-bisphosphate 3-kinase (PI3K) pathway in more than 20% of ovarian cancer (OC) patients. Therefore, PI3K therapies are under clinical evaluation for this subset of patients. Evidently, in clinical trials testing the efficacy of isoform-specific inhibitors of PI3K (PI3Ki), patients having a stable disease eventually relapse, as tumors become resistant to treatment. Hence, there is an urgent clinical need to develop new therapeutic combinations to improve the efficacy of PI3Ki in PIK3CA-driven OC patients. Here we identified the molecular mechanism that limits the efficacy of the beta-sparing PI3Ki, Taselisib (GDC0032), in PIK3CA-mutated OC cell lines (IGROV1 and OAW42) that acquired resistance to GDC0032. By comparing the molecular profile of GDC0032-sensitve and -resistant OC cell lines, we found that AKT/mTOR inhibition is required for GDC0032 efficacy. In resistant cells, the sustained activation of AKT/mTOR was regulated by the upregulation of the insulin growth factor 1 receptor (IGF1R). Knockdown of IGF1R re-sensitized cells to GDC0032 in vitro, and the combination of AEW541, an IGF1R inhibitor, with GDC0032 exhibited potent anti-tumor activity in vitro and in vivo. We further demonstrated that IGF1R regulates tumor cell proliferation in IGROV1 cells, whereas in OAW42, it determines autophagy as well. Overall, our findings suggest that the dual inhibition of PI3K and IGF1R may be considered as a new therapeutic strategy in PIK3CA-driven OC.
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DOI：
10.1186/s13058-016-0697-1
发表时间：
2016-04-05
期刊：
Breast cancer research : BCR
影响因子：
--
作者：
Leroy C;Ramos P;Cornille K;Bonenfant D;Fritsch C;Voshol H;Bentires-Alj M
通讯作者：
Bentires-Alj M
影响因子：
17.1
作者：
Elkabets M;Vora S;Juric D;Morse N;Mino-Kenudson M;Muranen T;Tao J;Campos AB;Rodon J;Ibrahim YH;Serra V;Rodrik-Outmezguine V;Hazra S;Singh S;Kim P;Quadt C;Liu M;Huang A;Rosen N;Engelman JA;Scaltriti M;Baselga J
通讯作者：
Baselga J
影响因子：
28.2
作者：
Juric D;Krop I;Ramanathan RK;Wilson TR;Ware JA;Sanabria Bohorquez SM;Savage HM;Sampath D;Salphati L;Lin RS;Jin H;Parmar H;Hsu JY;Von Hoff DD;Baselga J
通讯作者：
Baselga J
影响因子：
21.3
作者：
通讯作者：
--
影响因子：
5.7
作者：
de Lint, Klaas;Poell, Jos B.;Beijersbergen, Roderick L.
通讯作者：
Beijersbergen, Roderick L.