Concomitant targeting of the mTOR/MAPK pathways : novel therapeutic strategy in subsets of RICTOR/KRAS-altered non-small cell lung cancer
Despite a therapeutic paradigm shift into targeted-driven medicinal approaches, resistance to therapy remains a hallmark of lung cancer, driven by biological and molecular diversity. Using genomic and expression data from advanced non-small cell lung cancer (NSCLC) patients enrolled in the BATTLE-2 clinical trial, we identified RICTOR alterations in a subset of lung adenocarcinomas and found RICTOR expression to carry worse overall survival. RICTOR-altered cohort was significantly enriched in KRAS/MAPK axis mutations, suggesting a co-oncogenic driver role in these molecular settings. Using NSCLC cell lines, we showed that, distinctly in KRAS mutant backgrounds, RICTOR blockade impairs malignant properties and generates a compensatory enhanced activation of the MAPK pathway, exposing a unique therapeutic vulnerability. In vitro and in vivo concomitant pharmacologic inhibition of mTORC1/2 and MEK1/2 resulted in synergistic responses of anti-tumor effects. Our study provides evidence of a distinctive therapeutic opportunity in a subset of NSCLC carrying concomitant RICTOR/KRAS alterations.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2018 |
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| Erschienen: |
2018 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:9 |
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| Enthalten in: |
Oncotarget - 9(2018), 74 vom: 21. Sept., Seite 33995-34008 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Ruder, Dennis [VerfasserIn] |
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| Links: |
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| Themen: |
Journal Article |
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| Anmerkungen: |
Date Revised 17.11.2020 published: Electronic-eCollection Citation Status PubMed-not-MEDLINE |
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| doi: |
10.18632/oncotarget.26129 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM289725534 |
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| 245 | 1 | 0 | |a Concomitant targeting of the mTOR/MAPK pathways |b novel therapeutic strategy in subsets of RICTOR/KRAS-altered non-small cell lung cancer |
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| 520 | |a Despite a therapeutic paradigm shift into targeted-driven medicinal approaches, resistance to therapy remains a hallmark of lung cancer, driven by biological and molecular diversity. Using genomic and expression data from advanced non-small cell lung cancer (NSCLC) patients enrolled in the BATTLE-2 clinical trial, we identified RICTOR alterations in a subset of lung adenocarcinomas and found RICTOR expression to carry worse overall survival. RICTOR-altered cohort was significantly enriched in KRAS/MAPK axis mutations, suggesting a co-oncogenic driver role in these molecular settings. Using NSCLC cell lines, we showed that, distinctly in KRAS mutant backgrounds, RICTOR blockade impairs malignant properties and generates a compensatory enhanced activation of the MAPK pathway, exposing a unique therapeutic vulnerability. In vitro and in vivo concomitant pharmacologic inhibition of mTORC1/2 and MEK1/2 resulted in synergistic responses of anti-tumor effects. Our study provides evidence of a distinctive therapeutic opportunity in a subset of NSCLC carrying concomitant RICTOR/KRAS alterations | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a KRAS mutation | |
| 650 | 4 | |a MAPK pathway | |
| 650 | 4 | |a RICTOR gene abnormalities | |
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| 700 | 1 | |a Papadimitrakopoulou, Vassiliki |e verfasserin |4 aut | |
| 700 | 1 | |a Shien, Kazuhiko |e verfasserin |4 aut | |
| 700 | 1 | |a Behrens, Carmen |e verfasserin |4 aut | |
| 700 | 1 | |a Kalhor, Neda |e verfasserin |4 aut | |
| 700 | 1 | |a Chen, Huiqin |e verfasserin |4 aut | |
| 700 | 1 | |a Shen, Li |e verfasserin |4 aut | |
| 700 | 1 | |a Lee, J Jack |e verfasserin |4 aut | |
| 700 | 1 | |a Hong, Waun Ki |e verfasserin |4 aut | |
| 700 | 1 | |a Tang, Ximing |e verfasserin |4 aut | |
| 700 | 1 | |a Girard, Luc |e verfasserin |4 aut | |
| 700 | 1 | |a Minna, John D |e verfasserin |4 aut | |
| 700 | 1 | |a Diao, Lixia |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Jing |e verfasserin |4 aut | |
| 700 | 1 | |a Mino, Barbara |e verfasserin |4 aut | |
| 700 | 1 | |a Villalobos, Pamela |e verfasserin |4 aut | |
| 700 | 1 | |a Rodriguez-Canales, Jaime |e verfasserin |4 aut | |
| 700 | 1 | |a Hanson, Nana E |e verfasserin |4 aut | |
| 700 | 1 | |a Sun, James |e verfasserin |4 aut | |
| 700 | 1 | |a Miller, Vincent |e verfasserin |4 aut | |
| 700 | 1 | |a Greenbowe, Joel |e verfasserin |4 aut | |
| 700 | 1 | |a Frampton, Garrett |e verfasserin |4 aut | |
| 700 | 1 | |a Herbst, Roy S |e verfasserin |4 aut | |
| 700 | 1 | |a Baladandayuthapani, Veera |e verfasserin |4 aut | |
| 700 | 1 | |a Wistuba, Ignacio I |e verfasserin |4 aut | |
| 700 | 1 | |a Izzo, Julie G |e verfasserin |4 aut | |
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