Radiation Therapy As A Tool To Sensitize Hr Plus Breast Cancer And Mantle Cell Lymphoma To Cdk4/6 Inhibitors

Loss of cell cycle control is a common feature of most (if not all) human cancers. Thus, cell cycle genes that are frequently dysregulated in malignant cells, including CDK4 and CDK6, have attracted considerable attention as targets for the development of novel anticancer agents. This approach has culminated with the FDA approval of selective CDK4/6 inhibitors (e.g. palbociclib) for the treatment of hormone receptor (HR)+ breast cancer (BC). The same inhibitors are currently being tested in patients with a variety of solid and hematological tumors, including mantle cell lymphoma (MCL). However, not all BC and MCL patients achieve durable complete responses on CDK4/6 inhibitors, calling for the development of mechanism-based combination therapies. In this context, focal radiation therapy (RT) stands out as a promising therapeutic partner because both RT and CDK4/6 inhibitors have cytostatic/cytotoxic as well as immunostimulatory effects, but they operate with different mechanisms. We therefore decided to investigate the potential synergy/cooperation between RT and CDK4/6 inhibitors, with a particular focus on administration schedule, to inform the design of clinical trials testing the combination of these therapeutic agents in patients with HR+HER2-BC and MCL. We harnessed palbociclib-sensitive and -resistant MCL cells (MAVER-1 and MAVER-1R) and BC cells (MCF7 and MBA-MB-231) to investigate the ability of RT to synergize with palbociclib in vitro. In addition, we tested these combinations in vivo, in a unique immunocompetent mouse model of mammary carcinogenesis that recapitulates multiple immunobiological features of human HR+HER2-BC. In this model endogenous mammary carcinomas are driven by a slow-release progesterone pellet plus DMBA as an oral carcinogen. We first determined the lowest doses of RT and palbociclib that mediate robust short-term cytostatic/cytotoxic effects in BC and MCL cells. Optimized dose combinations and sequencing experiments pointed to RT followed by palbociclib as the approach with superior therapeutic potential, in vitro. This largely reflects the ability of palbociclib to induce G1 arrest of cells that escaped RT killing during G2/M arrest. In addition, low doses of RT were able to enhance palbociclib sensitivity in MAVER-1R cells. Both RT and palbociclib were active in the endogenous mammary carcinomas model, but failed to mediate disease eradication. In vivo experiments showed that RT preceding CDK4/6 inhibition achieved superior disease control, compared to other sequencing regimens. In conclusion, our results identified an optimal therapeutic sequence to combine RT and CDK4/6 inhibition in preclinical models of BC and MCL, providing a rational for combining stereotactic body RT and palbociclib in a clinical trial for patients with newly diagnosed HR+ oligo-metastatic BC (up to five metastatic lesions). Future directions include the evaluation of the immunostimulatory effects of RT plus palbociclib in the same models of BC and MCL. Supported by SU2C-Ziskin9s Award # ZP-6177. Citation Format: Giulia Petroni, Maurizio Di Liberto, Aitziber Buque Martinez, Selina Chen-Kiang, Lorenzo Galluzzi, Silvia C. Formenti. Radiation therapy as a tool to sensitize HR+ breast cancer and mantle cell lymphoma to CDK4/6 inhibitors [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4840.