Thibault Benoît, Thole Adrien, D'Angelo Romina, Basset Céline, Guillermet-Guibert Julie
CRCT, Université de Toulouse, Inserm, CNRS, Centre de Recherches en Cancérologie de Toulouse, Equipe SigDYN, 2 av Hubert Curien, Oncopole de Toulouse, Toulouse, France.
Labex TOUCAN, ANR, Toulouse, France.
Sci Rep. 2025 Feb 20;15(1):6265. doi: 10.1038/s41598-025-90714-9.
Peritoneal carcinomatosis in ovarian cancer is often associated with ascites where cancer cells grow as aggregates. Given the emerging evidence that multicellular growth enhances resistance to conventional therapies, and that patients frequently develop resistance to platinum salts, we investigated the efficiency of PI3K/Akt signalling pathway targeting in multicellular growth and its importance as a potential therapeutic target in cells resistant to platinum salts. Due to its importance in many cancers and to the frequent mutations of its encoding gene PIK3CA, we focused on targeting PI3Kα using BYL-719 (Alpelisib), an isoform-specific inhibitor already used in clinics. We used a panel of 3 ovarian cancer cell lines, SKOV-3, EFO-21 and OVCAR-3, which come from different histological origins and bear different mutations. PI3K targeting drugs inhibit the activity of the PI3K/Akt pathway in all tested ovarian cancer cell lines with a drastic reduction of the phosphorylation of Akt on the serine 473, regardless the histology or the mutational profile. We showed that when cultured in 3D aggregates, ovarian cancer cells are more resistant to the PI3Kα-specific inhibitor BYL-719 and cisplatin compared to 2D monolayers. BYL-719 synergizes with cisplatin in 3D cultures only in PIK3CA-mutated SKOV-3 cells. This drug combination leads to a major cytotoxicity in 3D aggregates of this cell line. Finally, BYL-719 in combination with cisplatin remains active in 3D aggregates of SKOV-3 cells co-cultured with mesenchymal stem cells. We have identified a signalling pathway of interest for the treatment of advanced ovarian cancer in vitro, which could limit the progression of this disease. These data pave the road to investigate whether PI3Kα-specific inhibitor BYL-719 should be proposed in combination with cisplatin, in priority in patients bearing a PIK3CA mutation.
卵巢癌中的腹膜癌转移通常与腹水相关，癌细胞以聚集体形式生长。鉴于新出现的证据表明多细胞生长增强了对传统疗法的抗性，且患者经常对铂盐产生抗性，我们研究了靶向PI3K/Akt信号通路在多细胞生长中的效率及其作为铂盐抗性细胞潜在治疗靶点的重要性。由于其在许多癌症中的重要性以及其编码基因PIK3CA的频繁突变，我们专注于使用已在临床中使用的亚型特异性抑制剂BYL-719（阿培利司）靶向PI3Kα。我们使用了一组3种卵巢癌细胞系，SKOV-3、EFO-21和OVCAR-3，它们来自不同的组织学起源且具有不同的突变。PI3K靶向药物在所有测试的卵巢癌细胞系中均抑制PI3K/Akt通路的活性，丝氨酸473位点的Akt磷酸化水平大幅降低，无论组织学类型或突变谱如何。我们发现，与二维单层培养相比，卵巢癌细胞在三维聚集体中培养时对PI3Kα特异性抑制剂BYL-719和顺铂更具抗性。仅在PIK3CA突变的SKOV-3细胞中，BYL-719在三维培养中与顺铂具有协同作用。这种药物组合在该细胞系的三维聚集体中导致主要的细胞毒性。最后，BYL-719与顺铂联合在与间充质干细胞共培养的SKOV-3细胞的三维聚集体中仍然具有活性。我们已经确定了一种在体外治疗晚期卵巢癌的感兴趣的信号通路，这可能会限制该疾病的进展。这些数据为研究是否应优先在携带PIK3CA突变的患者中联合使用PI3Kα特异性抑制剂BYL-719和顺铂铺平了道路。
