Concomitant Targeting of The Mtor/Mapk Pathways: Novel Therapeutic Strategy In Subsets of Non-Small Cell Lung Cancer

<p>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 <em>RICTOR</em> alterations (mutations, amplifications) in 17% of lung adenocarcinomas and found <em>RICTOR</em> expression correlates to worse overall survival. There was enrichment of MAPK pathway genetic aberrations in key oncogenes (e.g. <em>KRAS, BRAF, NF1</em>) associated with <em>RICTOR</em> altered cases, underscoring that RICTOR could serve as an important co-oncogenic driver in specific molecular settings. Moreover, we utilized a panel of <em>RICTOR</em> amplified NSCLC cell lines and found that <em>RICTOR</em> 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 <em>RICTOR</em> knockdown specifically in <em>KRAS</em> co-mutational settings, exposing a unique therapeutic vulnerability. Our <em>in vitro</em> and <em>in vivo</em> 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 <em>RICTOR/KRAS</em> alterations, further underscoring the need for proper patient selection to gain optimal therapeutic response.</p>

Name thesis:degree_name

Doctor of Philosophy (PhD)

Level thesis:degree_level

Dissertation (PhD)

Year dc:date.available

2016

Author dc:creator

• Ruder, Dennis

Contributors dc:contributor

• Ignacio I. Wistuba
• Veera Baladandayuthapani
• Juan Fueyo

• RICTOR
• KRAS
• Non-small cell lung cancer
• mTOR
• MAPK
• Cancer Biology
• Genetics
• Genomics
• Medicine and Health Sciences

Repository record dc:identifier

https://digitalcommons.library.tmc.edu/utgsbs_dissertations/725

OAI identifier oai:identifier

oai:digitalcommons.library.tmc.edu:utgsbs_dissertations-1770