Cancer Biology and Stem Cells Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.
Department of Medical Oncology, The Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
Clin Cancer Res. 2020 Aug 1;26(15):4120-4134. doi: 10.1158/1078-0432.CCR-19-1872. Epub 2020 Apr 3.
Although cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors significantly extend tumor response in patients with metastatic estrogen receptor-positive (ER) breast cancer, relapse is almost inevitable. This may, in part, reflect the failure of CDK4/6 inhibitors to induce apoptotic cell death. We therefore evaluated combination therapy with ABT-199 (venetoclax), a potent and selective BCL2 inhibitor.
BCL2 family member expression was assessed following treatment with endocrine therapy and the CDK4/6 inhibitor palbociclib. Functional assays were used to determine the impact of adding ABT-199 to fulvestrant and palbociclib in ER breast cancer cell lines, patient-derived organoid (PDO), and patient-derived xenograft (PDX) models. A syngeneic ER mouse mammary tumor model was used to study the effect of combination therapy on the immune system.
Triple therapy was well tolerated and produced a superior and more durable tumor response compared with single or doublet therapy. This was associated with marked apoptosis, including of senescent cells, indicative of senolysis. Unexpectedly, ABT-199 resulted in Rb dephosphorylation and reduced G-S cyclins, most notably at high doses, thereby intensifying the fulvestrant/palbociclib-induced cell-cycle arrest. Interestingly, a CRISPR/Cas9 screen suggested that ABT-199 could mitigate loss of Rb (and potentially other mechanisms of acquired resistance) to palbociclib. ABT-199 did not abrogate the favorable immunomodulatory effects of palbociclib in a syngeneic ER mammary tumor model and extended tumor response when combined with anti-PD1 therapy.
This study illustrates the potential for targeting BCL2 in combination with CDK4/6 inhibitors and supports investigation of combination therapy in ER breast cancer.
尽管细胞周期蛋白依赖性激酶 4 和 6（CDK4/6）抑制剂显著延长了转移性雌激素受体阳性（ER）乳腺癌患者的肿瘤反应，但几乎不可避免地会复发。这在一定程度上可能反映了 CDK4/6 抑制剂未能诱导细胞凋亡。因此，我们评估了与 ABT-199（venetoclax）联合治疗的效果，ABT-199 是一种有效的、选择性的 BCL2 抑制剂。
评估了内分泌治疗和 CDK4/6 抑制剂 palbociclib 治疗后 BCL2 家族成员的表达。功能测定用于确定在 ER 乳腺癌细胞系、患者来源的类器官（PDO）和患者来源的异种移植（PDX）模型中添加 ABT-199 对 fulvestrant 和 palbociclib 的影响。使用同源 ER 小鼠乳腺肿瘤模型研究联合治疗对免疫系统的影响。
与单一或双重治疗相比，三联治疗耐受性良好，产生了更好、更持久的肿瘤反应。这与明显的细胞凋亡有关，包括衰老细胞的凋亡，提示衰老细胞的溶酶体降解。出乎意料的是，ABT-199 导致 Rb 去磷酸化并减少 G1-S 周期蛋白，尤其是在高剂量下，从而增强了 fulvestrant/palbociclib 诱导的细胞周期阻滞。有趣的是，CRISPR/Cas9 筛选表明，ABT-199 可以减轻 palbociclib 引起的 Rb 丢失（和潜在的其他获得性耐药机制）。ABT-199 不会消除 palbociclib 在同源 ER 乳腺肿瘤模型中的有利免疫调节作用，并在与抗 PD1 治疗联合使用时延长肿瘤反应。
本研究说明了靶向 BCL2 与 CDK4/6 抑制剂联合的潜力，并支持在 ER 乳腺癌中进行联合治疗的研究。
