Dissertations and Theses (Open Access)

Author ORCID Identifier

0000-0003-0505-6815

Date of Graduation

8-2026

Document Type

Thesis (MS)

Program Affiliation

Molecular and Translational Biology

Degree Name

Masters of Science (MS)

Advisor/Committee Chair

John V. Heymach, MD, PhD

Committee Member

Don Gibbons, MD, PhD

Committee Member

Ralf Kittler, PhD

Committee Member

Marcelo Negrao, MD

Committee Member

Alexandre Reuben, PhD

Committee Member

Kyle Concannon, MD

Abstract

Strategies for overcoming ALK TKI resistance in ALK-fusion NSCLC

David Molkentine, Academic Advisor: John V. Heymach

Abstract

Before the emergence of targeted therapy, ALK-positive patients treated with standard chemotherapy had a median progression-free survival (PFS) in the range of 7-8 months. Over the last decade, the advent of ALK tyrosine kinase inhibitors (TKIs) produced significant improvements in the treatment of ALK-positive NSCLC, with currently over 60% of those receiving third-generation targeted therapy reaching 5-year PFS. However, for the remaining patients, on- and off-target therapeutic resistance can still limit time-on effectiveness. Therefore, to maximize efficacy, it is paramount to identify optimal next-line ALK-targeted therapies that consider any existing on-target mutations. Moreover, in cases of acquired resistance, we must devise effective combination strategies in an ALK TKI-refractory setting.

To address these clinical needs, we evaluated on-target resistance mutations by high-throughput drug screens and generated structure/function prediction models to facilitate clinical treatment decisions. Furthermore, through genetic screening, we identified novel on-target resistance mutations to third- and fourth-generation ALK TKIs. Additionally, to elucidate the underlying mechanisms of ALK TKI off-target resistance, we investigated treatment-resistance subpopulations leveraging a multi-omics approach. From these approaches, we identified ALK TKI-generation-agnostic resistance mechanisms that rely on RTK bypass via EGFR/HER3 signaling, and that targeting these drivers could favorably re-sensitize ALK TKI-resistant tumors.

Taken together, these data provide a mutation-specific drug-efficacy roadmap for multiple generations of ALK inhibitors, guiding optimal treatment strategies in the next-line clinical setting. Moreover, we elucidated compensatory upregulation of EGFR/HER3 and demonstrated that targeting these drivers in an ALK TKI-treatment-refractory setting can be an effective strategy for overcoming resistant disease.

Keywords

ALK, lorlatinib, neladalkib, iza-bren, lentimutate, EGFR, HER3, ADC

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Available for download on Saturday, August 14, 2027

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