Date of Award

1-1-2025

Degree Type

Dissertation

Degree Name

Doctor of Philosophy in Biological and Environmental Sciences

Specialization

Cell & Molecular Biology

Department

Cell & Molecular Biology

First Advisor

Gongqin Sun

Abstract

The latest edition of Global Cancer Statistics released by the American Cancer Society reported approximately 20 million newly diagnosed cancer cases worldwide in 2022 with 9.7 million deaths. This ranks cancer as the second leading cause of death worldwide. For the majority of cancer patients, the standard treatment approach is chemotherapy and/or radiation therapy, and while this has been successful in some patients, a lack of specificity to cancer cells causes severe side-effects when these agents damage healthy cells. Despite extensive efforts that have gone into developing targeted cancer therapeutics that block functions specific to cancer, they have not been broadly effective. In 2020, only 13.6% of all US cancer patients were genomically eligible for targeted therapies, and only 7.04% benefited from the treatment. Because the majority of cancers contain more than one oncogenic mutation, it is likely that the presence of additional oncogenic drivers is rendering cancer cells resistant to targeted monotherapies. In this study, I investigate mono-driver versus multi-driver oncogenesis in colorectal and triple negative breast cancer and suggest ways to combat multi-driver systems through the use of mechanism-based combination therapeutics.

In Manuscript I, I review clinical trials targeting the mitogen-activated protein kinase (MAPK) pathway and provide explanations as to why MAPK pathway inhibition is successful in some cancers and not in others despite containing the same mutations. I present clinical trial results for drugs targeting each step of the MAPK pathway to compare regression rates between cancer types. Results reveal that the majority of cancers do not benefit from MAPK pathway monotherapy.

In Manuscript II, I review the current landscape of targeting triple-negative breast cancer (TNBC), a deadly cancer that lacks broadly applicable targeted therapy options. I first discuss the current targeted therapy options available to TNBC patients and find that the majority of patients do not qualify for their administration. I then assess the presence of additional targets in TNBC that may prove to be promising in future therapeutic developments, such as the PI3K pathway, the MAPK pathway, and Src kinases. I find that clinical trials implementing a combination approach display improved clinical outcomes.

In Manuscript III, I perform a review and meta-analysis of available in vitro, in vivo, and clinical trial data on the promising dual Src/ABL inhibitor dasatinib. Dasatinib exemplifies both the greatest successes and largest disappointments in targeted cancer therapies, and as such, it can be used to compare characteristics of successful versus unsuccessful targeted therapy. I find that dasatinib’s clinical outcomes are dependent on its ability to either cytotoxically or cytostatically inhibit cancer cells. My findings support the use of dasatinib as a component of mechanism-based combination therapies.

In Manuscript IV, I investigate the role of BRAF mutations in colorectal cancer (CRC) and TNBC. I utilize two types of BRAF therapeutics, a small molecule inhibitor (dabrafenib) and a proteolysis-targeting chimera (SJF-0628), to categorize cancer cells as either mono-driver cells predominantly dependent on BRAF signaling or multi-driver cells supported by BRAF as well as additional oncogenic alterations. I find that mono-driver cancers can be effectively killed by either drug, whereas multi-driver cancers contain a mechanism of resistance. I reveal Src kinase and the PI3K pathway as two mechanisms of resistance to BRAF inhibition and/or degradation in CRC cells.

In Manuscript V, I investigate the role of BRAF mutations in CRC and TNBC. I first assess the effectiveness of the pan-KRAS inhibitor BI-2865 versus the MEK inhibitor trametinib and find that trametinib is more efficient at inhibiting cell proliferation and/or inducing apoptosis. Cells are categorized as either mono-driver cells predominantly dependent on BRAF signaling or multi-driver cells that contain mechanism(s) of resistance to MAPK pathway inhibition. In cells that only partially respond to KRAS and MEK monotherapies, I find that BRAF mutations, Src activation, and EGFR signaling are capable of conferring resistance to cell death.

In summary, this work provides valuable insights into the mechanisms of resistance to signaling-based targeted cancer therapeutics. It broadens our understanding of the role that MAPK pathway mutations play in conjunction with adjacent signaling pathways to promote the proliferation and survival of cancer. In doing so, it suggests ways to combat multi-driver oncogenesis by using a mechanism-based combination therapy approach in which targeted therapeutics are tailored to each cancer’s unique genetic profile.

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Available for download on Monday, November 17, 2025

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