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.
","abstract_html":"<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>","abstract_has_math":false,"creators":["Ruder, Dennis"],"institution":null,"degree_name":"Doctor of Philosophy (PhD)","degree_level":"Dissertation (PhD)","degree_discipline":null,"degree_department":null,"school":null,"contributors":["Ignacio I. Wistuba","Veera Baladandayuthapani","Juan Fueyo"],"advisors":[],"committee_chairs":[],"committee_members":[],"year":2016,"date_issued":"2016-12-01T08:00:00Z","date_published":"2016-12-01T08:00:00Z","updated_at":"2026-07-24T05:49:23Z","subjects":["RICTOR","KRAS","Non-small cell lung cancer","mTOR","MAPK","Cancer Biology","Genetics","Genomics","Medicine and Health Sciences"],"languages":[],"rights":[],"rights_urls":[],"identifier_entries":[]},"links":{"outbound_url":"https://digitalcommons.library.tmc.edu/utgsbs_dissertations/725","outbound_label":"Repository record","outbound_source":"dc:identifier"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor","label":"Contributor","values":["Ignacio I. Wistuba","Veera Baladandayuthapani","Juan Fueyo"]},{"key":"dc:creator","label":"Author","values":["Ruder, Dennis"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date.available","label":"Dc Date Available","values":["2018-12-15T08:00:00Z"]},{"key":"thesis:degree_level","label":"Degree Level","values":["Dissertation (PhD)"]},{"key":"thesis:degree_name","label":"Degree Name","values":["Doctor of Philosophy (PhD)"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["RICTOR","KRAS","Non-small cell lung cancer","mTOR","MAPK","Cancer Biology","Genetics","Genomics","Medicine and Health Sciences"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier","label":"Identifier","values":["https://digitalcommons.library.tmc.edu/utgsbs_dissertations/725"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description.abstract","label":"Abstract","values":["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.
"]},{"key":"dc:title","label":"Title","values":["Concomitant Targeting of The Mtor/Mapk Pathways: Novel Therapeutic Strategy In Subsets of Non-Small Cell Lung Cancer"]}]}],"canonical_facts":{"dc:contributor":["Ignacio I. Wistuba","Veera Baladandayuthapani","Juan Fueyo"],"dc:creator":["Ruder, Dennis"],"dc:date.available":["2018-12-15T08:00:00Z"],"dc:description.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.
"],"dc:identifier":["https://digitalcommons.library.tmc.edu/utgsbs_dissertations/725"],"dc:subject":["RICTOR","KRAS","Non-small cell lung cancer","mTOR","MAPK","Cancer Biology","Genetics","Genomics","Medicine and Health Sciences"],"dc:title":["Concomitant Targeting of The Mtor/Mapk Pathways: Novel Therapeutic Strategy In Subsets of Non-Small Cell Lung Cancer"],"thesis:degree_level":["Dissertation (PhD)"],"thesis:degree_name":["Doctor of Philosophy (PhD)"]},"updated_at":"2026-07-24T05:49:23Z"}