Department of Radiation Oncology, Weill Cornell Medical College, New York, NY, USA.
Healthcare Policy and Research, Weill Cornell Medical College, New York, NY, USA.
J Transl Med. 2023 Feb 10;21(1):110. doi: 10.1186/s12967-023-03964-4.
Preclinical evidence from us and others demonstrates that the anticancer effects of cyclin-dependent kinase 4/6 (CDK4/6) inhibitors can be enhanced with focal radiation therapy (RT), but only when RT is delivered prior to (rather than after) CDK4/6 inhibition. Depending on tumor model, cellular senescence (an irreversible proliferative arrest that is associated with the secretion of numerous bioactive factors) has been attributed beneficial or detrimental effects on response to treatment. As both RT and CDK4/6 inhibitors elicit cellular senescence, we hypothesized that a differential accumulation of senescent cells in the tumor microenvironment could explain such an observation, i.e., the inferiority of CDK4/6 inhibition with palbociclib (P) followed by RT (P→RT) as compared to RT followed by palbociclib (RT→P).
The impact of cellular senescence on the interaction between RT and P was assessed by harnessing female INK-ATTAC mice, which express a dimerizable form of caspase 8 (CASP8) under the promoter of cyclin dependent kinase inhibitor 2A (Cdkn2a, coding for p16), as host for endogenous mammary tumors induced by the subcutaneous implantation of medroxyprogesterone acetate (MPA, M) pellets combined with the subsequent oral administration of 7,12-dimethylbenz[a]anthracene (DMBA, D). This endogenous mouse model of HR mammary carcinogenesis recapitulates key immunobiological aspects of human HR breast cancer. Mice bearing M/D-driven tumors were allocated to RT, P or their combination in the optional presence of the CASP8 dimerizer AP20187, and monitored for tumor growth, progression-free survival and overall survival. In parallel, induction of senescence in vitro, in cultured human mammary hormone receptor (HR) adenocarcinoma MCF7 cells, triple negative breast carcinoma MDA-MB-231 cells and mouse HR mammary carcinoma TS/A cells treated with RT, P or their combination, was determined by colorimetric assessment of senescence-associated β-galactosidase activity after 3 or 7 days of treatment.
In vivo depletion of p16-expressing (senescent) cells ameliorated the efficacy of P→RT (but not that of RT→P) in the M/D-driven model of HR mammary carcinogenesis. Accordingly, P→RT induced higher levels of cellular senescence than R→TP in cultured human and mouse breast cancer cell lines.
Pending validation in other experimental systems, these findings suggest that a program of cellular senescence in malignant cells may explain (at least partially) the inferiority of P→RT versus RT→P in preclinical models of HR breast cancer.
我们和其他人的临床前证据表明，细胞周期蛋白依赖性激酶 4/6（CDK4/6）抑制剂的抗癌作用可以通过聚焦放射疗法（RT）增强，但只有在 RT 先于（而不是后于）CDK4/6 抑制时才会增强。根据肿瘤模型的不同，细胞衰老（一种与许多生物活性因子分泌相关的不可逆的增殖停滞）被归因于对治疗反应有益或有害的影响。由于 RT 和 CDK4/6 抑制剂都能引发细胞衰老，我们假设肿瘤微环境中衰老细胞的差异积累可以解释这种观察结果，即与 RT 后给予 palbociclib（RT→P）相比，palbociclib（P）先给予 RT（P→RT）的 CDK4/6 抑制效果较差。
通过利用雌性 INK-ATTAC 小鼠来评估细胞衰老对 RT 和 P 相互作用的影响，这些小鼠在 cyclin dependent kinase inhibitor 2A（编码 p16）启动子的控制下表达可二聚化的 caspase 8（CASP8），作为皮下植入 medroxyprogesterone acetate（MPA，M）丸剂和随后口服 7,12-二甲基苯并[a]蒽（DMBA，D）诱导的内源性乳腺肿瘤的宿主。这种 HR 乳腺致癌作用的内源性小鼠模型重现了人类 HR 乳腺癌的关键免疫生物学方面。携带 M/D 驱动肿瘤的小鼠被分配到 RT、P 或它们的组合中，在可选的情况下加入 CASP8 二聚体 AP20187，并监测肿瘤生长、无进展生存期和总生存期。同时，通过在体外培养的人乳腺激素受体（HR）腺癌 MCF7 细胞、三阴性乳腺癌 MDA-MB-231 细胞和小鼠 HR 乳腺腺癌 TS/A 细胞中用 RT、P 或它们的组合处理 3 或 7 天后，用比色法评估衰老相关β-半乳糖苷酶活性来确定细胞衰老的诱导。
体内耗尽表达 p16（衰老）的细胞改善了 P→RT（而非 RT→P）在 M/D 驱动的 HR 乳腺致癌作用模型中的疗效。因此，与 R→TP 相比，P→RT 在培养的人源和鼠源乳腺癌细胞系中诱导更高水平的细胞衰老。
在其他实验系统中得到验证之前，这些发现表明恶性细胞中的细胞衰老程序可能至少部分解释了 P→RT 与 RT→P 在 HR 乳腺癌的临床前模型中的劣势。
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