利用CDK4/6抑制劑的協同細胞毒殺與腫瘤微環境調控最佳化乳癌放射治療成效

Abstract

本研究旨在透過結合臨床觀察與前臨床實驗，評估CDK4/6抑制劑、放射治療及免疫療法之治療策略，以期達成乳癌治療的最佳化，提供個人化治療的依據。 在臨床分析中，我們針對接受系統性治療並合併不同放射治療方式的早期乳癌患者進行預後評估。研究結果顯示，單純鎖骨上淋巴區域放射治療的成效與更廣泛的區域性淋巴結放射治療（含內乳淋巴結）相當。此外，針對病理分期為N3的患者，額外增加腋下淋巴結放射治療並未顯著提升治療成效，暗示對於此類高風險患者，加強系統性治療可能較擴大放療範圍更具療效。 在前臨床實驗部分，我們探討CDK4/6抑制劑合併RT於荷爾蒙受體陽性、人類表皮生長因子受體2 (HER2)陰性乳癌的治療效果。研究顯示CDK4/6抑制劑可透過抑制ERK及NF-κB/c-Myc訊息傳導路徑，以及干擾DNA雙股斷裂修復，明顯提升細胞對放射治療的敏感性。此外，本研究進一步以具免疫功能的三陰性乳癌小鼠模式（4T1及EMT6），評估CDK4/6抑制劑、放射治療與抗PD-L1免疫療法的三合一治療策略。結果證實此三合一療法能有效抑制腫瘤生長，增加血液中干擾素-γ（IFN-γ）濃度，並促進CD4+ T細胞、CD8+ T細胞及M1型巨噬細胞浸潤腫瘤組織，成功將腫瘤微環境轉變為較具免疫刺激性的狀態。 整體而言，本研究成果凸顯CDK4/6抑制劑合併放射治療對於提升各種亞型乳癌的治療成效，以及促進免疫療法療效的潛力。上述前臨床研究結果值得未來進一步推展至臨床驗證，以期提升乳癌患者的整體預後及存活率。

This study aimed to optimize breast cancer treatment by integrating clinical insights and preclinical evaluations of CDK4/6 inhibitor, radiotherapy (RT), and immunotherapy, supporting personalized therapeutic strategies. Clinically, we analyzed outcomes in early-stage breast cancer patients receiving systemic therapy combined with various radiotherapy approaches. Supraclavicular radiotherapy (SCF-RT) alone showed comparable results to extensive regional nodal irradiation, including the internal mammary chain. Additionally, extending radiotherapy to axillary nodes did not improve outcomes for pathologically N3 patients, suggesting intensified systemic therapy might be more effective. Preclinically, we assessed CDK4/6 inhibitors combined with RT in HR-positive, HER2-negative breast cancer. CDK4/6 inhibitors increased radiosensitivity by suppressing ERK and NF-κB/c-Myc signaling and impairing DNA double-strand break repair. Furthermore, combining CDK4/6 inhibitors, RT, and anti-PD-L1 immunotherapy in immunocompetent triple-negative breast cancer (TNBC) mouse models effectively inhibited tumor growth, increased circulating IFN-γ levels, and enhanced immune cell infiltration, shifting the tumor microenvironment towards immunostimulation. Overall, this integrated approach highlights the promise of combining CDK4/6 inhibitors with RT to enhance therapeutic effects in breast cancer across various subtypes and improve the efficacy of immunotherapy. These promising preclinical results warrant further clinical investigation to potentially enhance treatment outcomes and patient survival.