Graduation Year

2023

Document Type

Dissertation

Degree

Ph.D.

Degree Name

Doctor of Philosophy (Ph.D.)

Degree Granting Department

Biology (Cell Biology, Microbiology, Molecular Biology)

Major Professor

Uwe Rix, Ph.D.

Committee Member

Andriy Marusyk, Ph.D.

Committee Member

Derek Duckett, Ph.D.

Committee Member

Eric Haura, M.D.

Committee Member

John Koomen, Ph.D.

Keywords

Proteomics, Bioinformatics, Cell-Type selective labeling with Amino acid Precursors (CTAP), Drug combination

Abstract

EML4-ALK fusion non-small cell lung cancer (NSCLC) represents a distinct subset of lung cancers that possesses unique molecular and clinical features, paving the way for targeted therapeutic interventions. Despite the promise of ALK-directed therapies, challenges such as metastasis at the time of diagnosis and treatment resistance persist, necessitating deeper research into the underlying mechanisms and potential solutions. In the context of these challenges, our study embarked on two specific objectives. The first goal, elucidated in Chapter 2, revolved around brain metastasis, an event critically facilitated by cell migration. Here, we assessed the anti-migratory activities of several clinical ALK inhibitors in NSCLC cells. Our observations emphasized ALK inhibitor brigatinib's superiority in mitigating migration compared to other ALK inhibitors, an attribute further probed by determining brigatinib's proteome-wide target profile in EML4-ALK fusion NSCLC cells. Key findings highlighted the kinases MARK2 and MARK3 as significant targets of brigatinib, leading to its pronounced anti-migratory capability. While as a tumor is heterocellular system and the trajectory of tumor progression is intricately shaped by the dynamic interplay between cancer cells and its microenvironment, in Chapter 3, our focus extended to the influence of cancer-associated fibroblasts (CAFs) on drug sensitivities. Through a systematic examination of EML4-ALK fusion NSCLC cell lines, a pronounced CAF-mediated drug resistance to ALK tyrosine kinase inhibitors was evident. Exploiting identified multi-faceted signaling mechanism, specifically HGF-MET signaling and the fibronectin-integrin axis, emerged as significant contributors to this resistance. Further pharmacological and genetic modulation strategies highlighted the potential of combined therapeutic regimens to counteract these resistance mechanisms, both in vitro and in vivo. Collectively, our research offers a comprehensive insight into the complexities of EML4-ALK fusion NSCLC, illuminating novel therapeutic avenues.

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