Graduation Date

Spring 5-9-2026

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Programs

Cellular & Integrative Physiology

First Advisor

Dr. Robert E. Lewis

Abstract

Small-cell lung carcinoma (SCLC) remains one of the most aggressive malignancies, driven by tumor-initiating cells (TICs) that underlie resistance and relapse after standard chemotherapy. Despite initial responses to cisplatin/etoposide, long-term success is limited by drug-tolerant persister (DTP) cells, often synonymous with TICs. Here, we identify the molecular scaffold KSR1 as a critical regulator of TIC function and chemoresistance across multiple SCLC subtypes. KSR1 ablation significantly reduces TIC frequency and prevents the emergence of drug-resistant clones after prolonged cisplatin exposure. In vivo, KSR1-deficient xenografts fail to form tumors under cisplatin treatment, indicating KSR1 loss sensitizes tumors to chemotherapy. Mechanistically, only wild-type KSR1—not ERK-binding-deficient mutants—rescues TIC function, implicating its scaffolding role in RAF/MEK/ERK signaling. Single-cell transcriptomics further revealed that KSR1 loss selectively depletes a TIC-like subpopulation marked by ANXA2, TMEM97, and SLC20A1 co-expression, defining a compartment amenable to therapeutic targeting or flow cytometric isolation. Notably, relapsed tumors that emerged following treatment discontinuation in KSR1 knockout xenograft acquired unique mutations, including in LSD1 and STAG1, suggesting compensatory resistance pathways. These findings establish KSR1 as a promising therapeutic vulnerability in SCLC, where disrupting its function may shift the balance from resistance to durable response.

Comments

2026 Copyright, the authors

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Available for download on Friday, January 22, 2027

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