The activity of a PI3K δ-sparing inhibitor, MEN1611, in non-small cell lung cancer cells with constitutive activation of the PI3K/AKT/mTOR pathway
BackgroundLung cancer remains the leading cause of cancer-related death worldwide. Targeted therapies with tyrosine kinase inhibitors (TKIs) result in improvement in survival for non-small cell lung cancer (NSCLC) with activating mutations of the epidermal growth factor receptor (EGFR). Unfortunatel...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2023-11-01
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| Series: | Frontiers in Oncology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fonc.2023.1283951/full |
| _version_ | 1797628006589530112 |
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| author | Giuliana Papoff Dario Presutti Valentina Fustaino Andrea Parente Clelia Calandriello Stefano Alemà Ferdinando Scavizzi Ferdinando Scavizzi Marcello Raspa Marcello Raspa Giuseppe Merlino Massimiliano Salerno Mario Bigioni Monica Binaschi Giovina Ruberti |
| author_facet | Giuliana Papoff Dario Presutti Valentina Fustaino Andrea Parente Clelia Calandriello Stefano Alemà Ferdinando Scavizzi Ferdinando Scavizzi Marcello Raspa Marcello Raspa Giuseppe Merlino Massimiliano Salerno Mario Bigioni Monica Binaschi Giovina Ruberti |
| author_sort | Giuliana Papoff |
| collection | DOAJ |
| description | BackgroundLung cancer remains the leading cause of cancer-related death worldwide. Targeted therapies with tyrosine kinase inhibitors (TKIs) result in improvement in survival for non-small cell lung cancer (NSCLC) with activating mutations of the epidermal growth factor receptor (EGFR). Unfortunately, most patients who initially respond to EGFR-TKI ultimately develop resistance to therapy, resulting in cancer progression and relapse. Combination therapy is today a common strategy for the treatment of tumors to increase the success rate, improve the outcome and survival of patients, and avoid the selection of resistant cancer cells through the activation of compensatory pathways. In NSCLC, the phosphoinositide-3-kinase/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway has been heavily implicated in both tumorigenesis and the progression of disease.ObjectivesIn this study, we investigated the efficacy of a PI3K δ-sparing inhibitor, MEN1611, in models of NSCLC sensitive and resistant to EGFR inhibitors (erlotinib and gefitinib) with a wild-type PIK3CA gene.MethodsWe performed functional, biochemical, and immunohistochemistry studies.ResultsWe demonstrated good efficacy of MEN1611 in NSCLC devoid of PIK3CA gene mutations but with constitutive activation of the PI3K/AKT pathway and its synergistic effect with gefitinib both in vitro and in vivo.ConclusionsOverall, this preclinical study indicates that the inhibitor could be a candidate for the treatment of NSCLC with an erlotinib/gefitinib-resistant phenotype and constitutive activation of the PI3K/AKT pathway, a phenotype mimicked by our model system. |
| first_indexed | 2024-03-11T10:32:24Z |
| format | Article |
| id | doaj.art-280dc1bb29754467928f7742e2628ec3 |
| institution | Directory Open Access Journal |
| issn | 2234-943X |
| language | English |
| last_indexed | 2024-03-11T10:32:24Z |
| publishDate | 2023-11-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Oncology |
| spelling | doaj.art-280dc1bb29754467928f7742e2628ec32023-11-14T13:50:04ZengFrontiers Media S.A.Frontiers in Oncology2234-943X2023-11-011310.3389/fonc.2023.12839511283951The activity of a PI3K δ-sparing inhibitor, MEN1611, in non-small cell lung cancer cells with constitutive activation of the PI3K/AKT/mTOR pathwayGiuliana Papoff0Dario Presutti1Valentina Fustaino2Andrea Parente3Clelia Calandriello4Stefano Alemà5Ferdinando Scavizzi6Ferdinando Scavizzi7Marcello Raspa8Marcello Raspa9Giuseppe Merlino10Massimiliano Salerno11Mario Bigioni12Monica Binaschi13Giovina Ruberti14Institute of Biochemistry and Cell Biology, National Research Council (IBBC-CNR), Monterotondo, Rome, ItalyInstitute of Biochemistry and Cell Biology, National Research Council (IBBC-CNR), Monterotondo, Rome, ItalyInstitute of Biochemistry and Cell Biology, National Research Council (IBBC-CNR), Monterotondo, Rome, ItalyInstitute of Biochemistry and Cell Biology, National Research Council (IBBC-CNR), Monterotondo, Rome, ItalyInstitute of Biochemistry and Cell Biology, National Research Council (IBBC-CNR), Monterotondo, Rome, ItalyInstitute of Biochemistry and Cell Biology, National Research Council (IBBC-CNR), Monterotondo, Rome, ItalyInstitute of Biochemistry and Cell Biology, National Research Council (IBBC-CNR), Monterotondo, Rome, ItalyEuropean Mouse Mutant Archive (EMMA), INFRAFRONTIER, Monterotondo Mouse Clinic, IBBC-CNR, Monterotondo, Rome, ItalyInstitute of Biochemistry and Cell Biology, National Research Council (IBBC-CNR), Monterotondo, Rome, ItalyEuropean Mouse Mutant Archive (EMMA), INFRAFRONTIER, Monterotondo Mouse Clinic, IBBC-CNR, Monterotondo, Rome, ItalyMenarini Ricerche S.p.A., Rome, ItalyMenarini Ricerche S.p.A., Rome, ItalyMenarini Ricerche S.p.A., Rome, ItalyMenarini Ricerche S.p.A., Rome, ItalyInstitute of Biochemistry and Cell Biology, National Research Council (IBBC-CNR), Monterotondo, Rome, ItalyBackgroundLung cancer remains the leading cause of cancer-related death worldwide. Targeted therapies with tyrosine kinase inhibitors (TKIs) result in improvement in survival for non-small cell lung cancer (NSCLC) with activating mutations of the epidermal growth factor receptor (EGFR). Unfortunately, most patients who initially respond to EGFR-TKI ultimately develop resistance to therapy, resulting in cancer progression and relapse. Combination therapy is today a common strategy for the treatment of tumors to increase the success rate, improve the outcome and survival of patients, and avoid the selection of resistant cancer cells through the activation of compensatory pathways. In NSCLC, the phosphoinositide-3-kinase/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway has been heavily implicated in both tumorigenesis and the progression of disease.ObjectivesIn this study, we investigated the efficacy of a PI3K δ-sparing inhibitor, MEN1611, in models of NSCLC sensitive and resistant to EGFR inhibitors (erlotinib and gefitinib) with a wild-type PIK3CA gene.MethodsWe performed functional, biochemical, and immunohistochemistry studies.ResultsWe demonstrated good efficacy of MEN1611 in NSCLC devoid of PIK3CA gene mutations but with constitutive activation of the PI3K/AKT pathway and its synergistic effect with gefitinib both in vitro and in vivo.ConclusionsOverall, this preclinical study indicates that the inhibitor could be a candidate for the treatment of NSCLC with an erlotinib/gefitinib-resistant phenotype and constitutive activation of the PI3K/AKT pathway, a phenotype mimicked by our model system.https://www.frontiersin.org/articles/10.3389/fonc.2023.1283951/fullNSCLCPI3K inhibitorEGFR-TKIsdrug-resistancecombination therapy |
| spellingShingle | Giuliana Papoff Dario Presutti Valentina Fustaino Andrea Parente Clelia Calandriello Stefano Alemà Ferdinando Scavizzi Ferdinando Scavizzi Marcello Raspa Marcello Raspa Giuseppe Merlino Massimiliano Salerno Mario Bigioni Monica Binaschi Giovina Ruberti The activity of a PI3K δ-sparing inhibitor, MEN1611, in non-small cell lung cancer cells with constitutive activation of the PI3K/AKT/mTOR pathway Frontiers in Oncology NSCLC PI3K inhibitor EGFR-TKIs drug-resistance combination therapy |
| title | The activity of a PI3K δ-sparing inhibitor, MEN1611, in non-small cell lung cancer cells with constitutive activation of the PI3K/AKT/mTOR pathway |
| title_full | The activity of a PI3K δ-sparing inhibitor, MEN1611, in non-small cell lung cancer cells with constitutive activation of the PI3K/AKT/mTOR pathway |
| title_fullStr | The activity of a PI3K δ-sparing inhibitor, MEN1611, in non-small cell lung cancer cells with constitutive activation of the PI3K/AKT/mTOR pathway |
| title_full_unstemmed | The activity of a PI3K δ-sparing inhibitor, MEN1611, in non-small cell lung cancer cells with constitutive activation of the PI3K/AKT/mTOR pathway |
| title_short | The activity of a PI3K δ-sparing inhibitor, MEN1611, in non-small cell lung cancer cells with constitutive activation of the PI3K/AKT/mTOR pathway |
| title_sort | activity of a pi3k δ sparing inhibitor men1611 in non small cell lung cancer cells with constitutive activation of the pi3k akt mtor pathway |
| topic | NSCLC PI3K inhibitor EGFR-TKIs drug-resistance combination therapy |
| url | https://www.frontiersin.org/articles/10.3389/fonc.2023.1283951/full |
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