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Transl. Med."],"published-print":{"date-parts":[[2025,12,17]]},"abstract":"<jats:p>\n                    Combined CDK4\/6 inhibitor (CDK4\/6i) and endocrine therapy (ET) improves outcomes in advanced estrogen receptor\u2013positive (ER\n                    <jats:sup>+<\/jats:sup>\n                    ) breast cancer, but emergence of resistance to this combination underscores the pressing need for alternative therapeutic strategies. A promising approach involves adding an inhibitor of the PI3K\/AKT\/mTOR pathway to the standard combined CDK4\/6i and ET, but selecting the most effective inhibitors and their optimal combinations has proven to be challenging. Here, we compared the efficacy of various triple combinations using single- or dual-point PI3K\/AKT\/mTOR pathway inhibitors in breast cancer cell lines, cell line xenografts, patient-derived xenografts, and organoids resistant to CDK4\/6i and ET and exhibiting\n                    <jats:italic toggle=\"yes\">PIK3CA<\/jats:italic>\n                    ,\n                    <jats:italic toggle=\"yes\">PTEN<\/jats:italic>\n                    , or\n                    <jats:italic toggle=\"yes\">AKT1<\/jats:italic>\n                    mutations.\n                    <jats:italic toggle=\"yes\">PIK3CA<\/jats:italic>\n                    -mutant,\n                    <jats:italic toggle=\"yes\">PTEN<\/jats:italic>\n                    \u2013wild type, CDK4\/6i-resistant, and ET-resistant models required the addition of the dual PI3K\/mTOR inhibitor gedatolisib to effectively impede tumor growth by blocking the HIF-1\u03b1 pathway through both mTORC1 inhibition and PI3K\/AKT-mediated modulation of GSK3\u03b1\/\u03b2 activity. Conversely,\n                    <jats:italic toggle=\"yes\">PIK3CA<\/jats:italic>\n                    \u2013wild type,\n                    <jats:italic toggle=\"yes\">PTEN<\/jats:italic>\n                    -null cells benefited from triple combinations incorporating either the AKT inhibitor capivasertib or the dual mTORC1\/2 inhibitor sapanisertib to block tumor growth. In addition, gedatolisib reduced viability of\n                    <jats:italic toggle=\"yes\">PIK3CA<\/jats:italic>\n                    - or\n                    <jats:italic toggle=\"yes\">AKT1<\/jats:italic>\n                    -mutant and\n                    <jats:italic toggle=\"yes\">PTEN<\/jats:italic>\n                    \u2013wild type CDK4\/6i-resistant patient-derived organoids compared with the \u03b1-specific PI3K inhibitor alpelisib. Our data support the higher efficacy of gedatolisib over alpelisib in ER\n                    <jats:sup>+<\/jats:sup>\n                    breast tumors harboring alterations of the PI3K\/AKT\/mTOR pathway including\n                    <jats:italic toggle=\"yes\">PIK3CA<\/jats:italic>\n                    or\n                    <jats:italic toggle=\"yes\">AKT1<\/jats:italic>\n                    mutations.\n                  <\/jats:p>","DOI":"10.1126\/scitranslmed.adp5088","type":"journal-article","created":{"date-parts":[[2025,12,17]],"date-time":"2025-12-17T19:00:39Z","timestamp":1765998039000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":8,"title":["Dual PI3K\/mTOR inhibition is required to combat resistance to CDK4\/6 inhibitor and endocrine therapy in\n                    <i>PIK3CA<\/i>\n                    -mutant breast cancer"],"prefix":"10.1126","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2266-9349","authenticated-orcid":true,"given":"Carla L.","family":"Alves","sequence":"first","affiliation":[{"name":"Cancer Research Unit, Department of Molecular Medicine, University of Southern Denmark, 5230 Odense, Denmark."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2877-5134","authenticated-orcid":true,"given":"Leena","family":"Karimi","sequence":"additional","affiliation":[{"name":"Cancer Research Unit, Department of Molecular Medicine, University of Southern Denmark, 5230 Odense, Denmark."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4468-6900","authenticated-orcid":true,"given":"Mikkel G.","family":"Terp","sequence":"additional","affiliation":[{"name":"Cancer Research Unit, Department of Molecular Medicine, University of Southern Denmark, 5230 Odense, Denmark."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mie K.","family":"Jakobsen","sequence":"additional","affiliation":[{"name":"Cancer Research Unit, Department of Molecular Medicine, University of Southern Denmark, 5230 Odense, Denmark."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3113-1671","authenticated-orcid":true,"given":"Fiona H.","family":"Zhou","sequence":"additional","affiliation":[{"name":"Garvan Institute of Medical Research, Darlinghurst, Sydney, New South Wales 2010, Australia."},{"name":"St. Vincent's Clinical School, University of New South Wales, Sydney, New South Wales 2052, Australia."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-1055-4503","authenticated-orcid":true,"given":"Benedetta","family":"Policastro","sequence":"additional","affiliation":[{"name":"Cancer Research Unit, Department of Molecular Medicine, University of Southern Denmark, 5230 Odense, Denmark."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nikoline","family":"Nissen","sequence":"additional","affiliation":[{"name":"Cancer Research Unit, Department of Molecular Medicine, University of Southern Denmark, 5230 Odense, Denmark."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lene E.","family":"Johansen","sequence":"additional","affiliation":[{"name":"Cancer Research Unit, Department of Molecular Medicine, University of Southern Denmark, 5230 Odense, Denmark."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6376-621X","authenticated-orcid":true,"given":"Tina","family":"Ravnsborg","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, University of Southern Denmark, 5230 Odense, Denmark."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leila","family":"Eshraghi","sequence":"additional","affiliation":[{"name":"Garvan Institute of Medical Research, Darlinghurst, Sydney, New South Wales 2010, Australia."},{"name":"St. Vincent's Clinical School, University of New South Wales, Sydney, New South Wales 2052, Australia."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sana","family":"Tamboowala","sequence":"additional","affiliation":[{"name":"Garvan Institute of Medical Research, Darlinghurst, Sydney, New South Wales 2010, Australia."},{"name":"St. Vincent's Clinical School, University of New South Wales, Sydney, New South Wales 2052, Australia."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1862-8528","authenticated-orcid":true,"given":"Ole N.","family":"Jensen","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, University of Southern Denmark, 5230 Odense, Denmark."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8065-8838","authenticated-orcid":true,"given":"Elgene","family":"Lim","sequence":"additional","affiliation":[{"name":"Garvan Institute of Medical Research, Darlinghurst, Sydney, New South Wales 2010, Australia."},{"name":"St. Vincent's Clinical School, University of New South Wales, Sydney, New South Wales 2052, Australia."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3927-5135","authenticated-orcid":true,"given":"Henrik J.","family":"Ditzel","sequence":"additional","affiliation":[{"name":"Cancer Research Unit, Department of Molecular Medicine, University of Southern Denmark, 5230 Odense, Denmark."},{"name":"Department of Oncology, Odense University Hospital, 5000 Odense, Denmark."},{"name":"Department of Clinical Research, University of Southern Denmark, 5250 Odense, Denmark."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"221","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1607303"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1505270"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.3390\/ijms21176400"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2114663"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1001\/jamaoncol.2019.4782"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-15-0728"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1158\/1535-7163.MCT-17-0537"},{"key":"e_1_3_2_9_2","first-page":"6055","article-title":"PIK3CA mutations contribute to fulvestrant resistance in ER-positive breast cancer","volume":"11","author":"Huang D.","year":"2019","unstructured":"D. Huang, L. Tang, F. Yang, J. Jin, X. Guan, PIK3CA mutations contribute to fulvestrant resistance in ER-positive breast cancer. Am. J. Transl. Res. 11, 6055\u20136065 (2019).","journal-title":"Am. J. Transl. Res."},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1109653"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1813904"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-20-3652"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(19)30817-4"},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2404625"},{"key":"e_1_3_2_15_2","doi-asserted-by":"crossref","unstructured":"R. Layman R. Wesolowski H. Han J. M. Specht E. M. Stringer-Reasor E. C. Dees P. Kabos I. A. Mayer U. Vaishampayan J. Lu K. Gogineni A. Bardia A. F. Schott M. M. Abu-Khalaf D. Hawkins B. Sullivan I. Gorbatchevsky H. S. Rugo Abstract PD13-02: Phase Ib expansion study of gedatolisib in combination with palbociclib and endocrine therapy in women with ER+ metastatic breast cancer. Cancer Res. 82 (Suppl. 4) PD13-02 (2022).","DOI":"10.1158\/1538-7445.SABCS21-PD13-02"},{"key":"e_1_3_2_16_2","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2018.36.15_suppl.1040"},{"key":"e_1_3_2_17_2","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-21-2652"},{"key":"e_1_3_2_18_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccr.2014.05.020"},{"key":"e_1_3_2_19_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-25422-9"},{"key":"e_1_3_2_20_2","doi-asserted-by":"publisher","DOI":"10.1002\/cac2.12425"},{"key":"e_1_3_2_21_2","doi-asserted-by":"publisher","DOI":"10.1186\/s13058-020-01320-8"},{"key":"e_1_3_2_22_2","doi-asserted-by":"publisher","DOI":"10.1158\/1535-7163.MCT-15-0143"},{"key":"e_1_3_2_23_2","doi-asserted-by":"publisher","DOI":"10.1038\/nchembio.183"},{"key":"e_1_3_2_24_2","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-12-1141"},{"key":"e_1_3_2_25_2","doi-asserted-by":"publisher","DOI":"10.1158\/1535-7163.MCT-11-0824-T"},{"key":"e_1_3_2_26_2","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-12-3072"},{"key":"e_1_3_2_27_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1903765"},{"key":"e_1_3_2_28_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1607303"},{"key":"e_1_3_2_29_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(15)00613-0"},{"key":"e_1_3_2_30_2","doi-asserted-by":"publisher","DOI":"10.1093\/annonc\/mdy155"},{"key":"e_1_3_2_31_2","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2018.78.9909"},{"key":"e_1_3_2_32_2","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2017.73.7585"},{"key":"e_1_3_2_33_2","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-16-2653"},{"key":"e_1_3_2_34_2","doi-asserted-by":"publisher","DOI":"10.1158\/1535-7163.MCT-13-0639"},{"key":"e_1_3_2_35_2","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-20-3624"},{"key":"e_1_3_2_36_2","doi-asserted-by":"publisher","DOI":"10.1038\/s43018-021-00229-1"},{"key":"e_1_3_2_37_2","doi-asserted-by":"crossref","unstructured":"K. L. Jhaveri S.-A. Im C. Saura D. Juric S. Loibl K. Kalinsky P. Schmid S. Loi E. Thanopoulou N. Shankar G. Lei T. Stout K. E. Hutchinson J. Schutzman C. Song N. C. Turner Abstract GS03-13: Inavolisib or placebo in combination with palbociclib and fulvestrant in patients with PIK3CA-mutated hormone receptor-positive HER2-negative locally advanced or metastatic breast cancer: Phase III INAVO120 primary analysis. Cancer Res. 84 (Suppl. 9) GS03-13 (2023).","DOI":"10.1158\/1538-7445.SABCS23-GS03-13"},{"key":"e_1_3_2_38_2","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2011.36.1360"},{"key":"e_1_3_2_39_2","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-11-0039"},{"key":"e_1_3_2_40_2","doi-asserted-by":"publisher","DOI":"10.1007\/s11523-011-0176-7"},{"key":"e_1_3_2_41_2","doi-asserted-by":"publisher","DOI":"10.1158\/1538-7445.AM2012-2227"},{"key":"e_1_3_2_42_2","doi-asserted-by":"publisher","DOI":"10.1158\/1538-7445.AM2012-3749"},{"key":"e_1_3_2_43_2","doi-asserted-by":"publisher","DOI":"10.1158\/1535-7163.MCT-14-0330"},{"key":"e_1_3_2_44_2","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.00015-07"},{"key":"e_1_3_2_45_2","doi-asserted-by":"publisher","DOI":"10.1007\/s11033-015-3858-x"},{"key":"e_1_3_2_46_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2007.06.009"},{"key":"e_1_3_2_47_2","doi-asserted-by":"publisher","DOI":"10.1158\/1535-7163.MCT-15-0365"},{"key":"e_1_3_2_48_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature17963"},{"key":"e_1_3_2_49_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00280-017-3343-4"},{"key":"e_1_3_2_50_2","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-17-3440"},{"key":"e_1_3_2_51_2","doi-asserted-by":"publisher","DOI":"10.1042\/BJ20130342"},{"key":"e_1_3_2_52_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2016.06.004"},{"key":"e_1_3_2_53_2","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-19-3324"},{"key":"e_1_3_2_54_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2214131"},{"key":"e_1_3_2_55_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1314124110"},{"key":"e_1_3_2_56_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccr.2009.04.012"},{"key":"e_1_3_2_57_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature11412"},{"key":"e_1_3_2_58_2","doi-asserted-by":"publisher","DOI":"10.1001\/jamaoncol.2019.0034"},{"key":"e_1_3_2_59_2","doi-asserted-by":"publisher","DOI":"10.3747\/co.22.2393"},{"key":"e_1_3_2_60_2","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2023.41.16_suppl.TPS1118"},{"key":"e_1_3_2_61_2","doi-asserted-by":"publisher","DOI":"10.1186\/s13058-020-01318-2"},{"key":"e_1_3_2_62_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2017.11.010"},{"key":"e_1_3_2_63_2","doi-asserted-by":"publisher","DOI":"10.1074\/mcp.M112.025585"},{"key":"e_1_3_2_64_2","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jproteome.0c00508"}],"container-title":["Science Translational Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.science.org\/doi\/pdf\/10.1126\/scitranslmed.adp5088","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,12,17]],"date-time":"2025-12-17T19:00:50Z","timestamp":1765998050000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.science.org\/doi\/10.1126\/scitranslmed.adp5088"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,12,17]]},"references-count":63,"journal-issue":{"issue":"829","published-print":{"date-parts":[[2025,12,17]]}},"alternative-id":["10.1126\/scitranslmed.adp5088"],"URL":"https:\/\/doi.org\/10.1126\/scitranslmed.adp5088","relation":{},"ISSN":["1946-6234","1946-6242"],"issn-type":[{"value":"1946-6234","type":"print"},{"value":"1946-6242","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,12,17]]},"assertion":[{"value":"2024-03-28","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-05-30","order":1,"name":"revised","label":"Revised","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-11-10","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-12-17","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"eadp5088"}}