Author ORCID Identifier

0000-0003-0504-2747

Date of Graduation

5-2024

Document Type

Dissertation (PhD)

Program Affiliation

Cancer Biology

Degree Name

Doctor of Philosophy (PhD)

Advisor/Committee Chair

Scott Kopetz

Committee Member

Lawrence Kwong

Committee Member

Anil Sood

Committee Member

Traver Hart

Committee Member

John Paul Shen

Committee Member

Wenyi Wang

Abstract

Colorectal cancer is the second leading cause of cancer-related deaths and the third most common cancer in the United States. Although KRAS is mutated in 50% of patients with metastatic CRC (mCRC), it has historically been a challenging therapeutic target. The recent approval of novel covalent inhibitors selective for KRASG12C mutation have entered the clinic, which has not only marked a major milestone in cancer drug discovery but has also intensified efforts to directly target other KRAS mutations that have also successfully entered the clinic. However, treatment-associated resistance mechanisms have long threatened to attenuate clinical benefit through either adaptive or acquired resistance. To better understand the impact of this mutation on this patient population, this dissertation has sought to characterize the clinical and molecular features using our MD Anderson Cancer Center cohort. To delineate the mechanisms of adaptive and acquired resistance, we have characterized our KRASG12C mCRC patient-derived xenograft models that were treated with KRASG12C targeted therapies and on study paired biopsies from progressing patients. We examine the role of SHP2 as a mechanism of adaptive resistance and investigate the efficacy of a KRASG12C and SHP2 inhibitor combination in our in vivo models. We show that this combination has better efficacy than the well-established KRASG12C and EGFR inhibitor combination. Moreover, we identify YAP-TAZ TEAD as a mechanism of acquired resistance in both our in vivo resistant models and in progressing patients. Finally, we interrogate novel YAP and pan-TEAD inhibitors for their clinical potential to overcome emergent resistance to KRASG12C and EGFR inhibitors for the goal of optimizing outcomes for patients with mCRC.

Keywords

Colorectal Cancer, CRC, KRASG12C, resistance, SHP2, YAP, TEAD, drug therapeutics, cancer informatics

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Available for download on Wednesday, April 30, 2025

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