Soler Adriana, Figueiredo Ana M, Castel Pau, Martin Laura, Monelli Erika, Angulo-Urarte Ana, Milà-Guasch Maria, Viñals Francesc, Baselga Jose, Casanovas Oriol, Graupera Mariona
Vascular Signaling Laboratory, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain.
Human Oncology and Pathogenesis Program (HOPP), Memorial Sloan Kettering Cancer Center, New York, New York.
Clin Cancer Res. 2016 Dec 1;22(23):5805-5817. doi: 10.1158/1078-0432.CCR-15-3051. Epub 2016 May 25.
Mutations in the PI3K pathway occur in 16% of patients with pancreatic neuroendocrine tumors (PanNETs), which suggests that these tumors are an exciting setting for PI3K/AKT/mTOR pharmacologic intervention. Everolimus, an mTOR inhibitor, is being used to treat patients with advanced PanNETs. However, resistance to mTOR-targeted therapy is emerging partially due to the loss of mTOR-dependent feedback inhibition of AKT. In contrast, the response to PI3K inhibitors in PanNETs is unknown.
In the current study, we assessed the frequency of PI3K pathway activation in human PanNETs and in RIP1-Tag2 mice, a preclinical tumor model of PanNETs, and we investigated the therapeutic efficacy of inhibiting PI3K in RIP1-Tag2 mice using a combination of pan (GDC-0941) and p110α-selective (GDC-0326) inhibitors and isoform-specific PI3K kinase-dead-mutant mice.
Human and mouse PanNETs showed enhanced pAKT, pPRAS40, and pS6 positivity compared with normal tissue. Although treatment of RIP1-Tag2 mice with GDC-0941 led to reduced tumor growth with no impact on tumor vessels, the selective inactivation of the p110α PI3K isoform, either genetically or pharmacologically, reduced tumor growth as well as vascular area. Furthermore, GDC-0326 reduced the incidence of liver and lymph node metastasis compared with vehicle-treated mice. We also demonstrated that tumor and stromal cells are implicated in the antitumor activity of GDC-0326 in RIP1-Tag2 tumors.
Our data provide a rationale for p110α-selective intervention in PanNETs and unravel a new function of this kinase in cancer biology through its role in promoting metastasis. Clin Cancer Res; 22(23); 5805-17. ©2016 AACR.
16%的胰腺神经内分泌肿瘤（PanNETs）患者存在PI3K通路突变，这表明这些肿瘤是PI3K/AKT/mTOR药物干预的一个令人兴奋的研究对象。依维莫司是一种mTOR抑制剂，正用于治疗晚期PanNETs患者。然而，对mTOR靶向治疗的耐药性正在出现，部分原因是AKT的mTOR依赖性反馈抑制作用丧失。相比之下，PanNETs对PI3K抑制剂的反应尚不清楚。
在本研究中，我们评估了人类PanNETs和PanNETs临床前肿瘤模型RIP1-Tag2小鼠中PI3K通路激活的频率，并使用泛PI3K抑制剂（GDC-0941）和p110α选择性抑制剂（GDC-0326）以及亚型特异性PI3K激酶失活突变小鼠，研究了在RIP1-Tag2小鼠中抑制PI3K的治疗效果。
与正常组织相比，人类和小鼠的PanNETs显示出增强的pAKT、pPRAS40和pS6阳性。虽然用GDC-0941治疗RIP1-Tag2小鼠可导致肿瘤生长减缓且对肿瘤血管无影响，但通过基因或药物方法选择性失活p110α PI3K亚型可减少肿瘤生长以及血管面积。此外，与用赋形剂处理的小鼠相比，GDC-0326降低了肝和淋巴结转移的发生率。我们还证明肿瘤和基质细胞与GDC-0326在RIP1-Tag2肿瘤中的抗肿瘤活性有关。
我们的数据为PanNETs中p110α选择性干预提供了理论依据，并揭示了该激酶在癌症生物学中的新功能，即其在促进转移中的作用。临床癌症研究；22(23)；5805 - 17。©2016美国癌症研究协会。
