Date of Graduation

12-2016

Document Type

Dissertation (PhD)

Program Affiliation

Human and Molecular Genetics

Degree Name

Doctor of Philosophy (PhD)

Advisor/Committee Chair

Ignacio I. Wistuba

Committee Member

Veera Baladandayuthapani

Committee Member

Juan Fueyo

Committee Member

Faye M. Johnson

Committee Member

Jonathan M. Kurie

Committee Member

Jeffrey N. Myers

Abstract

Over the last decade, a paradigm-shift in lung cancer therapy has evolved into targeted-driven medicinal approaches. However, patients frequently relapse and develop resistance to available therapies. Herein, we utilized genomic mutation data from advanced chemorefractory non-small cell lung cancer (NSCLC) patients enrolled in the Biomarker-Integrated Approaches of Targeted Therapy for Lung Cancer Elimination (BATTLE-2) clinical trial to characterize novel actionable genomic alterations potentially of clinical relevance. We identified RICTOR alterations (mutations, amplifications) in 17% of lung adenocarcinomas and found RICTOR expression correlates to worse overall survival. There was enrichment of MAPK pathway genetic aberrations in key oncogenes (e.g. KRAS, BRAF, NF1) associated with RICTOR altered cases, underscoring that RICTOR could serve as an important co-oncogenic driver in specific molecular settings. Moreover, we utilized a panel of RICTOR amplified NSCLC cell lines and found that RICTOR genetic blockade impaired malignant properties seen by reduced effects on cell survival and tumorigenicity potential. We uncovered a compensatory activation of the MAPK signaling pathway following RICTOR knockdown specifically in KRAS co-mutational settings, exposing a unique therapeutic vulnerability. Our in vitro and in vivo data testing concomitant pharmacologic inhibition of both pathways (PI3K/AKT/mTOR and MAPK) via AZD2014 (mTORC1/2 inhibitor) and selumetinib (MEK1/2) resulted in synergistic responses of antitumor effects. Given the large population of patients affected by NSCLC, our study provides a treatment rationale for a specific subset of patients who may benefit from genomic stratification based on RICTOR/KRAS alterations, further underscoring the need for proper patient selection to gain optimal therapeutic response.

Keywords

RICTOR, KRAS, Non-small cell lung cancer, mTOR, MAPK

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