Broege Aaron, Rossetti Stefano, Sen Adrish, De La Forest Ann, Davis Laura, Seibel Megan, Menon Arul S, Stokke Sydney, Macaulay Allison, Molden Jhomary, Laing Lance
Celcuity, Inc., 16305 36th Ave N, Suite 100, Minneapolis, MN 55446, USA.
Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720, USA.
Int J Mol Sci. 2025 Jun 18;26(12):5844. doi: 10.3390/ijms26125844.
Treatment with endocrine therapy (ET) in combination with CDK4/6 inhibitors has improved the outcome of patients with hormone receptor (HR)+/HER2- advanced breast cancer (ABC), but most patients eventually experience disease progression. Since the PI3K-AKT-mTOR (PAM), estrogen receptor (ER), and cyclin-dependent kinase (CDK) pathways are interdependent drivers of HR+/HER2- breast cancer (BC), the simultaneous inhibition of these pathways is expected to enhance anti-tumor control. Here we investigated the molecular and cellular effects of gedatolisib, a multi-target kinase inhibitor of the PAM pathway currently being evaluated in Phase 3 clinical trials, combined with fulvestrant and/or palbociclib in BC cell models. We found that the gedatolisib/fulvestrant/palbociclib triplet inhibited BC cell growth significantly more than the single agents or the palbociclib/fulvestrant doublet, both in vitro and vivo. Specifically, the triplet combination counteracted adaptive responses associated with single drug treatment, such as the reactivation of the CDK-RB-E2F pathway after palbociclib treatment, and inhibited multiple cellular functions, such as cell cycle progression, cell survival, protein synthesis, and glucose metabolism. The triplet combination was effective in treatment-naïve BC cell lines as well as in cell lines adapted to palbociclib and/or fulvestrant, regardless of genetic alterations. Our findings provide a mechanistic rationale for conducting clinical studies evaluating gedatolisib in combination with CDK4/6 inhibitors and ET in HR+/HER2- ABC.
内分泌治疗（ET）联合CDK4/6抑制剂可改善激素受体（HR）阳性/人表皮生长因子受体2（HER2）阴性晚期乳腺癌（ABC）患者的预后，但大多数患者最终仍会出现疾病进展。由于PI3K-AKT-mTOR（PAM）、雌激素受体（ER）和细胞周期蛋白依赖性激酶（CDK）信号通路是HR阳性/HER2阴性乳腺癌（BC）相互依存的驱动因素，同时抑制这些信号通路有望增强抗肿瘤控制效果。在此，我们在BC细胞模型中研究了目前正在进行3期临床试验评估的PAM信号通路多靶点激酶抑制剂吉地替尼联合氟维司群和/或哌柏西利的分子和细胞效应。我们发现，无论在体外还是体内，吉地替尼/氟维司群/哌柏西利三联疗法对BC细胞生长的抑制作用均显著强于单药或哌柏西利/氟维司群双联疗法。具体而言，三联疗法可抵消与单药治疗相关的适应性反应，如哌柏西利治疗后CDK-RB-E2F信号通路的重新激活，并抑制多种细胞功能，如细胞周期进程、细胞存活、蛋白质合成和葡萄糖代谢。无论基因改变如何，三联疗法对未经治疗的BC细胞系以及对哌柏西利和/或氟维司群产生适应性的细胞系均有效。我们的研究结果为开展评估吉地替尼联合CDK4/6抑制剂和ET用于HR阳性/HER2阴性ABC的临床研究提供了机制依据。
