Inhibiting BRAF/EGFR/MEK suppresses cancer stemness and drug resistance of primary colorectal cancer cells
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Astha Lamichhane1, Gary D. Luker2, Seema Agarwal3 and Hossein Tavana1
1 Department of Biomedical Engineering, The University of Akron, Akron, OH 44325, USA
2 Department of Radiology, Microbiology and Immunology, Biomedical Engineering, University of Michigan, Ann Arbor, MI 48105, USA
3 Department of Pathology, Biochemistry, Molecular and Cellular Biology, Georgetown University, Washington, DC 20007, USA
|Hossein Tavana,||email:||[email protected]|
Keywords: drug resistance; cancer stem cells; patient-derived tumor model; colorectal cancer; combination treatment
Received: May 02, 2023 Accepted: September 21, 2023 Published: October 04, 2023
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 BRAFmut and KRASmut 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.
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