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However, acquired resistance to these therapies frequently leads to disease progression. As such, it is critical to identify the mechanisms by which resistance to CDK4\/6-based therapies is acquired and also identify therapeutic strategies to overcome resistance.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>In this study, we developed and characterized multiple in vitro and in vivo models of acquired resistance to CDK4\/6-based therapies. Resistant models were screened by reverse phase protein array (RPPA) for cell signaling changes that are activated in resistance.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      We show that either a direct loss of Rb or loss of dependence on Rb signaling confers cross-resistance to inhibitors of CDK4\/6, while PI3K\/mTOR signaling remains activated. Treatment with the p110\u03b1-selective PI3K inhibitor, alpelisib (BYL719), completely blocked the progression of acquired CDK4\/6 inhibitor-resistant xenografts in the absence of continued CDK4\/6 inhibitor treatment in models of both\n                      <jats:italic>PIK3CA<\/jats:italic>\n                      mutant and wild-type ER+\/HER2\u2212 breast cancer. Triple combination therapy against PI3K:CDK4\/6:ER prevented and\/or delayed the onset of resistance in treatment-naive ER+\/HER2\u2212 breast cancer models.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>These data support the clinical investigation of p110\u03b1-selective inhibitors of PI3K, such as alpelisib, in patients with ER+\/HER2\u2212 breast cancer who have progressed on CDK4\/6:ER-based therapies. Our data also support the investigation of PI3K:CDK4\/6:ER triple combination therapy to prevent the onset of resistance to the combination of endocrine therapy plus CDK4\/6 inhibition.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s13058-020-01320-8","type":"journal-article","created":{"date-parts":[[2020,8,14]],"date-time":"2020-08-14T08:14:20Z","timestamp":1597392860000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":125,"title":["Targeting activated PI3K\/mTOR signaling overcomes acquired resistance to CDK4\/6-based therapies in preclinical models of hormone receptor-positive breast cancer"],"prefix":"10.1186","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7408-1091","authenticated-orcid":false,"given":"Neil A.","family":"O\u2019Brien","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martina S. 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O\u2019Brien: Novartis\u2014research funding.Martina S.J. McDermott: none to declareDylan Conklin: none to declareTong Luo: none to declareRaul Ayala: none to declareSuruchi Salgar: none to declareKevin Chau: none to declareEmmanuelle DiTomaso: former Novartis employeeNaveen Babbar: full-time Novartis employeeFaye Su: full-time Novartis employeeAlex Gaither: former Novartis employeeSara A. Hurvitz: clinical research funding paid to UCLA from Eli Lilly, Novartis, and PfizerRonald Linnartz: full-time Novartis employeeKristine Rose: full-time Novartis employeeSamit Hirawat: former Novartis employeeDennis J. Slamon: Pfizer\u2014stock ownership, research funding, and travel expenses. Novartis\u2014honoraria, consulting advisory role, research funding, and travel expenses. Eli Lilly\u2014consulting advisory role","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"89"}}