Author ORCID Identifier

https://orcid.org/0009-0001-3456-2998


Date Available

7-20-2025

Year of Publication

2025

Document Type

Doctoral Dissertation

Degree Name

Doctor of Philosophy (PhD)

College

Medicine

Department/School/Program

Toxicology and Cancer Biology

Faculty

Yekaterina Zaytseva

Faculty

Qiou Wei

Abstract

Colorectal cancer (CRC) is the second leading cause of cancer death worldwide. The overall incidence rates of CRC have decreased in those over 50, but there is an increasing incidence rate in those under 50. Risk factors for CRC include diet, family history, and a sedentary lifestyle. Early detection of CRC is key to patient survival and treatment response. Localized CRC has a survival rate of 90% and allows for surgical resection and chemotherapy. The 5-year survival for metastatic CRC (mCRC) is significantly reduced to around 14%. Despite early detection, 50% of patients will develop metastasis after surgical resection and only 20% of patients will achieve remission with metastatic disease. Resistance to current therapeutic options in CRC is a major concern and understanding this mechanism is crucial to improve patient outcomes.

Even though efficient therapeutics have been developed, there is still a rise in diagnoses among younger populations. V-raf murine sarcoma viral oncogene homolog B1 (BRAF) and Kirsten rat sarcoma viral oncogene homolog (KRAS) are proto-oncogenes that are a part of the mitogen activated protein kinase (MAPK) pathway, and are often mutated in many cancers, and significantly in CRC. The most common BRAF mutation is BRAFV600E, which occurs in 10-15% of CRC cases. The BRAFV600E mutation usually occurs early in tumorigenesis and is associated with an aggressive phenotype and poorer patient outcomes, potentially resulting from constitutive MAPK signaling and uncontrolled cell growth, possibly through reactivation of epidermal growth factor (EGFR). Single-agent BRAF inhibition has proven ineffective due to acquired resistance. Current FDA approved therapy for mCRC BRAFV600E CRC is combining encorafenib (BRAF inhibitor) with cetuximab (EGFR inhibitor). Despite benefits of this approved therapy, the increased efficacy is short-term. A second generation BRAF inhibitor, PLX8394, is known as a paradox breaker, and has shown promising potential. Acquired resistance to BRAF inhibitors highlights the importance of combinational therapy to reduce MAPK pathway reactivation and overcome therapeutic resistance.

Literature suggests that resistance to BRAF-targeted therapy may be associated with an increase in de novo lipid synthesis. Fatty acid synthase (FASN), a key enzyme in de novo lipid synthesis, has been shown to be upregulated in many cancers and contributes to cell progression and metastasis. FASN overexpression is associated with advanced stages of CRC and results in poorer prognosis. Studies have shown that pharmacological inhibition of FASN using TVB3664 in CRC, decreases cell proliferation, diminishes metastatic capabilities, and inhibits tumor angiogenesis in vivo.

My studies have demonstrated that the development of resistance to BRAF-targeted therapy involves increased proliferation of CRC in vitro and in vivo, promotion of invasion through loss of E-cadherin, upregulation of multiple cytokine levels, including VEGF, lipid metabolism, β-oxidation and lipid storage, and most importantly increased expression of FASN. FASN inhibition using TVB3664 increases efficacy of PLX8394 in parental cells but is not effective in PLX8394-resistant cells. However, pharmacological inhibition of FASN postpones development of resistance to PLX8394 and encorafenib by inhibiting the cell cycle progression via a decrease in pRb, E2F, and Cyclin D1. Additionally, clinical data show that tumor tissues from BRAFV600E CRC patients that exhibit high FASN expression have higher expression of cell cycle-associated genes. Collectively, my studies suggest that upregulation of FASN promotes the development of resistance to PLX8394 and encorafenib through FASN-pRb-E2F-driven cell cycle progression. The addition of FASN inhibitors at the start of BRAF-targeted therapy regimen can increase the efficacy and postpone the acquired resistance in BRAFV600E mCRC. Therefore, targeting FASN as part of BRAF-targeted therapy can be an effective therapeutic strategy in patients with BRAFV600E CRC.

Digital Object Identifier (DOI)

https://doi.org/10.13023/etd.2025.282

Funding Information

SRFs are supported by National Cancer Institute grant P30 CA177558

National Cancer Institute training grant T32 CA165990 (MEG)

R01 CA249734 (YYX)

Colorectal Cancer Alliance grant (YYZ)

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