Targeting Mitochondrial Fusion in Colorectal Cancer

Colorectal cancer ranks second in cancer-related mortality for both men and women in the United States. Nearly half of colorectal cancer patients exhibit aberrant activation of the MAPK/ERK pathway due to gain-of-function mutations in the BRAF and KRAS genes. Among these patients, those with the BRAF V600E mutation have the poorest prognosis. Therapeutic combinations of FDA-approved BRAF inhibitors with other agents targeting the MAPK/ERK pathway marginally increase survival, suggesting that blocking this pathway activates prosurvival mechanisms in colorectal cancer cells. The goal of this proposal is to identify these prosurvival mechanisms and design rational therapeutic combinations to enhance the efficacy of BRAF inhibitors by blocking these mechanisms in colorectal cancer cells harboring the BRAF V600E mutation. Our preliminary studies identified that inhibition of the MAPK/ERK pathway promotes mitochondrial fusion. We recently discovered that increased mitochondrial fusion acts as a prosurvival mechanism in Acute Myeloid Leukemia cells by enhancing mitophagy, an autophagic process that clears damaged mitochondria in response to BH3 mimetics treatment. Promisingly, pharmacologic inhibition of mitochondrial fusion combined with BRAF inhibitors synergistically eradicated colorectal cancer cells with BRAF V600E mutations. The proposed work will dissect the contribution of mitochondrial fusion to the survival of colorectal cancer cells upon treatment with MAPK/ERK pathway inhibitors and assess the therapeutic potential of targeting mitochondrial fusion in murine and organoid models of colorectal cancer. Additionally, this proposal outlines my career development plan for transitioning into a successful independent investigator. This plan includes participation in scientific and career development meetings, workshops, and coursework to gain more experience in cancer and chemical biology, and to hone my mentorship and leadership skills. Collectively, this research award is expected to profoundly impact the treatment of colorectal cancer, providing conceptual groundwork, preliminary data, and experimental tools that will lay the foundation for developing clinical trials combining mitochondrial fusion inhibitors with existing BRAF inhibitors and for launching my career as an independent investigator. Project Number: 1K22CA299833-01A1 | Fiscal Year: 2026 | NIH Institute/Center: National Cancer Institute (NCI) | Principal Investigator: Emmanouil Zacharioudakis | Institution: PURDUE UNIVERSITY, WEST LAFAYETTE, IN | Award Amount: $190,944 | Activity Code: K22 | Study Section: Special Emphasis Panel[ZRG1 BTC-K (50)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11302236