Department of Biomedical Engineering, The University of Akron, Akron, OH 44325, USA.
Department of Radiology, Microbiology and Immunology, Biomedical Engineering, University of Michigan, Ann Arbor, MI 48105, USA.
Oncotarget. 2023 Oct 4;14:879-889. doi: 10.18632/oncotarget.28517.
Drug resistance is a major barrier against successful treatments of cancer patients. Gain of stemness under drug pressure is a major mechanism that renders treatments ineffective. Identifying approaches to target cancer stem cells (CSCs) is expected to improve treatment outcomes for patients. To elucidate the role of cancer stemness in resistance of colorectal cancer cells to targeted therapies, we developed spheroid cultures of patient-derived BRAF and KRAS tumor cells and studied resistance mechanisms to inhibition of MAPK pathway through phenotypic and gene and protein expression analysis. We found that treatments enriched the expression of CSC markers CD166, ALDH1A3, CD133, and LGR5 and activated PI3K/Akt pathway in cancer cells. We examined various combination treatments to block these activities and found that a triple combination against BRAF, EGFR, and MEK significantly reduced stemness and activities of oncogenic signaling pathways. This study demonstrates the feasibility of blocking stemness-mediated drug resistance and tumorigenic activities in colorectal cancer.
耐药性是癌症患者成功治疗的主要障碍。在药物压力下获得干性是使治疗无效的主要机制。鉴定针对癌症干细胞（CSC）的方法有望改善患者的治疗效果。为了阐明癌症干性在结直肠癌细胞对靶向治疗耐药性中的作用，我们通过表型和基因及蛋白表达分析，建立了患者来源的 BRAF 和 KRAS 肿瘤细胞的球体培养物，并研究了 MAPK 通路抑制的耐药机制。我们发现，治疗方法富集了 CSC 标志物 CD166、ALDH1A3、CD133 和 LGR5 的表达，并激活了 PI3K/Akt 通路。我们检查了各种联合治疗方法来阻断这些活性，发现针对 BRAF、EGFR 和 MEK 的三联治疗显著降低了干性和致癌信号通路的活性。这项研究证明了阻断结直肠癌中干性介导的耐药性和致瘤活性的可行性。
