Inhibiting BRAF/EGFR/MEK suppresses cancer stemness and drug resistance of primary colorectal cancer cells

• Published in: Oncotarget Vol. 14; no. 1; pp. 879 - 889
• Main Authors: Lamichhane, Astha, Luker, Gary D, Agarwal, Seema, Tavana, Hossein
• Format: Journal Article
• Language: English
• Published: United States Impact Journals LLC 04-10-2023
• Subjects: Colorectal Neoplasms - drug therapy; Colorectal Neoplasms - genetics; ErbB Receptors; Humans; Mitogen-Activated Protein Kinase Kinases; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins B-raf - genetics; Research Paper; colorectal cancer; cancer stem cells; drug resistance; combination treatment; patient-derived tumor model
• ISSN: 1949-2553; 1949-2553
• 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.