Lim Sung Hee, Lee Song-Yi, Hong Jung Yong, Lee Jeeyun, Kim Seung Tae
Division of Hematology-Oncology, Department of Medicine, Sungkyunkwan University, Samsung Medical Center, Seoul, Korea.
Transl Cancer Res. 2024 Jul 31;13(7):3695-3703. doi: 10.21037/tcr-24-20. Epub 2024 Jul 12.
In v-raf murine sarcoma viral oncogene homolog B1 (BRAF)-mutant colorectal cancer (CRC), encorafenib-cetuximab has been established as standard second-line therapy, but not all patients respond and the duration of response is relatively short. Overcoming intrinsic or acquired resistance to BRAF/EGFR inhibitors is crucial for enhancing treatment outcomes in metastatic BRAF-mutated CRC. The aim of the study is to investigate the resistance mechanisms in BRAF-mutant CRC patient refractory to BRAF/EGFR targeted therapy.
We established patient-derived cells (PDCs) from a patient with BRAF/PTEN-mutant metastatic colon cancer who progressed rapidly on encorafenib plus cetuximab. To explore potential treatment options for inherent resistance caused by simultaneous PTEN mutation in BRAF-mutated CRC, we conducted cell viability assays using PDCs treated with encorafenib-cetuximab in combination with a cyclin-dependent kinase-4 and 6 (CDK4/6) inhibitor.
The patient's tumor had concurrent PTEN loss-of-function alteration at diagnosis and PDCs were generated from ascites after resistance to the BRAF/EGFR inhibitor. The PDCs were resistant to the encorafenib-cetuximab combination even at a high concentration of cetuximab (up to 500 µg/mL). Adding the CDK4/6 inhibitor, ribociclib, to encorafenib-cetuximab showed a synergistic effect in a proliferation assay. Ribociclib plus encorafenib-cetuximab represented a significantly lower expression of Ki-67 compared to the dual combination alone. An MTS assay showed that triplet therapy with ribociclib, encorafenib, and cetuximab suppressed cell viability more efficiently than the two-drug combinations. Investigating the combined effect of triplet therapy using the calculated combination index (CI) showed that ribociclib had a synergistic effect with encorafenib-cetuximab when applied to PDCs with a concurrent BRAF/PTEN mutation.
Our results suggest that combining the CDK4/6 inhibitor with the BRAF/EGFR inhibitor might be a novel treatment strategy for concomitant BRAF and PTEN-mutant CRC.
在v-raf鼠肉瘤病毒癌基因同源物B1（BRAF）突变的结直肠癌（CRC）中，恩考芬尼-西妥昔单抗已被确立为标准二线治疗方案，但并非所有患者都有反应，且反应持续时间相对较短。克服对BRAF/表皮生长因子受体（EGFR）抑制剂的内在或获得性耐药对于提高转移性BRAF突变型CRC的治疗效果至关重要。本研究的目的是探讨对BRAF/EGFR靶向治疗难治的BRAF突变型CRC患者的耐药机制。
我们从一名BRAF/磷酸酶和张力蛋白同源物（PTEN）突变的转移性结肠癌患者中建立了患者来源细胞（PDC），该患者在接受恩考芬尼加西妥昔单抗治疗后病情迅速进展。为了探索BRAF突变型CRC中因PTEN同时突变导致的固有耐药的潜在治疗选择，我们使用恩考芬尼-西妥昔单抗联合细胞周期蛋白依赖性激酶4和6（CDK4/6）抑制剂处理的PDC进行了细胞活力测定。
该患者的肿瘤在诊断时同时存在PTEN功能丧失改变，并且在对BRAF/EGFR抑制剂耐药后从腹水中产生了PDC。即使在高浓度西妥昔单抗（高达500μg/mL）下，PDC对恩考芬尼-西妥昔单抗联合用药也具有耐药性。在增殖试验中，将CDK4/6抑制剂瑞博西尼添加到恩考芬尼-西妥昔单抗中显示出协同作用。与单独的双联组合相比，瑞博西尼加恩考芬尼-西妥昔单抗使Ki-67的表达显著降低。一种四唑盐比色法（MTS）试验表明，瑞博西尼、恩考芬尼和西妥昔单抗三联疗法比两药组合更有效地抑制细胞活力。使用计算得出的联合指数（CI）研究三联疗法的联合效果表明，当应用于同时存在BRAF/PTEN突变的PDC时，瑞博西尼与恩考芬尼-西妥昔单抗具有协同作用。
我们的结果表明，将CDK4/6抑制剂与BRAF/EGFR抑制剂联合使用可能是BRAF和PTEN同时突变的CRC的一种新治疗策略。
