Graduation Year
2024
Document Type
Dissertation
Degree
Ph.D.
Degree Name
Doctor of Philosophy (Ph.D.)
Degree Granting Department
Molecular Biosciences
Major Professor
Andriy Marusyk, Ph.D.
Committee Member
Eric Lau, Ph.D.
Committee Member
Karen Mann, Ph.D.
Committee Member
David Basanta, Ph.D.
Keywords
ALK+, KRASG12C, Lung cancer, Stromal resistance, Targeted therapies
Abstract
The introduction of targeted therapies has resulted in immense success in treating lung cancer patients, where many patients experience long-term remission. Yet, the tumors relapse into an advanced state of disease, and ultimately, treatment failure. This can be ascribed to incomplete eradication of tumor cells by targeted therapies, which enables the residual tumor cells to propagate resistant tumors and cause subsequent relapse in patients. Therapy sensitivity is influenced not only by cell-intrinsic mechanisms but also by inputs from the stromal microenvironment. Despite widespread recognition of the stromal microenvironment's role in modulating therapy sensitivity, its contribution to therapeutic responses in vivo remains insufficiently characterized. Here, we investigated the contribution of stroma-mediated resistance in xenograft models of ALK+ NSCLC against ALK-targeted therapies. We report that proximity to the stroma partially protects the tumor cells against ALK-targeted therapy. This protective effect is evident during both remission and relapse, indicating the importance of stroma-mediated resistance in both persistence of tumor cells and in therapeutic resistance. Our study reports that spatial aspects of stromal-mediated resistance effects, such as stromal abundance and dispersal, can influence the responses to the therapy. From a molecular mechanistic perspective, the protective effect of the stromal niche involves multiple mechanisms, including growth factors and extracellular matrix components, resulting in multifactorial effects that protect the tumor cells from therapy. Consequently, targeting individual resistance mechanisms can improve responses to targeted therapy but is insufficient to counteract the protective effects of stroma. Using both in vitro and in vivo validation experiments, we demonstrated that targeting shared collateral sensitivities of therapy-persister cells represents a more effective therapeutic approach. Together, our findings suggest that stroma-mediated resistance significantly contributes to both residual and progressive disease, underscoring limitations of strategies that target single resistance mechanisms. Our studies emphasize the need for a broader approach that considers the multifactorial nature of therapy resistance in overcoming therapy resistance.
Scholar Commons Citation
Desai, Bina, "Overcoming Microenvironmentally Mediated Resistance in Targetable Non-Small Cell Lung Cancer" (2024). USF Tampa Graduate Theses and Dissertations.
https://digitalcommons.usf.edu/etd/11176
