Semester

Summer

Date of Graduation

2022

Document Type

Dissertation

Degree Type

PhD

College

School of Pharmacy

Department

Pharmaceutical Sciences

Committee Chair

Lori Hazlehurst

Committee Co-Chair

Yon Rojanasakul

Committee Member

Yon Rojanasakul

Committee Member

Marina Galvez Peralta

Committee Member

Mike Ruppert

Committee Member

Werner Geldenhuys

Committee Member

Gangqing Hu

Abstract

Lung cancer remains the deadliest of all cancers due to the high mutational burden associated with the disease. Combating mutational drivers and drug resistance proves to be essential in the development of novel therapies to improve patient outcomes. A first-in-class cyclic peptide known as MTI-101 has been shown to induce necrotic cell death in a caspase independent manner. MTI-101 was derived from the linear peptide known as HYD1 that was found in a high throughput screen to block cell adhesion with the extracellular matrix. The compound was further optimized and cyclized to the currently used MTI-101 that was found to be substantially more potent across multiple cancer types. In this dissertation, we sought to determine biomarkers of resistance to MTI-101 coupled with cell signaling pathways that become activated with the introduction of MTI-101 along with their contribution to cell death. The development of isogenic resistant lung cancer cell lines were utilized as tools to aid in the delineation of MTI-101’s effects on lung cancer. Chronic exposure to MTI-101 leading to the acquired resistance demonstrated changes of cell state to a clinically favorable mesenchymal-to-epithelial transition (MET) genotype and phenotype using in vitro and in vivomodels. Selectivity of MTI-101 towards cancer cells was revealed with a lack of efficacy in healthy bronchial epithelial cells treated with a lethal cancer cell dose of MTI-101. Acquired resistance was found to have collateral sensitivity to standard of care agents while used as single agents and synergistic activity on wildtype cancer cells when used in combination with MTI-101. Simultaneous activation of second messengers calcium and cAMP alluded toward GPCR activation with MTI-101 treatment. Attenuation of calcium signaling protected from MTI-101 induced cell death while activation of calcium signaling exacerbated death. Decreased drug binding likely explained the lack of downstream signaling and protection from cell death in acquired resistant lung cancer cell lines. Incorporation of therapies that alter cell state and calcium signaling pathways in combination with current standard of care agents remain vital in positioning novel therapy options in the clinic for improved patient survival with the deadliest cancer.

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