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oai:recercat.cat:11351/86982025-10-25T05:37:44Zcom_2072_378072com_2072_378040col_2072_378100

AKT-mTORC1 reactivation is the dominant resistance driver for PI3Kβ/AKT inhibitors in PTEN-null breast cancer and can be overcome by combining with Mcl-1 inhibitors Dunn, Shanade Eberlein, Cath Yu, Jason Ong, Swee Hoe Yelland, Urs Serra Elizalde, Violeta Gris Oliver, Albert Institut Català de la Salut [Dunn S] Wellcome Sanger Institute, Cambridge, UK. Bioscience, Early Oncology, AstraZeneca, Cambridge, UK. [Eberlein C, Yelland U] Bioscience, Early Oncology, AstraZeneca, Alderley Park, UK. [Yu J] Wellcome Sanger Institute, Cambridge, UK. Molecular Biology of Metabolism Lab, The Francis Crick Institute, London, UK. [Gris-Oliver A, Serra V] Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. [Ong SH] Wellcome Sanger Institute, Cambridge, UK Vall d'Hebron Barcelona Hospital Campus Mama - Càncer - Tractament Medicaments antineoplàstics - Ús terapèutic Resistència als medicaments DISEASES::Neoplasms::Neoplasms by Site::Breast Neoplasms Other subheadings::Other subheadings::Other subheadings::/drug therapy PHENOMENA AND PROCESSES::Physiological Phenomena::Pharmacological and Toxicological Phenomena::Pharmacological Phenomena::Drug Resistance::Drug Resistance, Neoplasm CHEMICALS AND DRUGS::Chemical Actions and Uses::Pharmacologic Actions::Therapeutic Uses::Antineoplastic Agents Other subheadings::Other subheadings::/therapeutic use ENFERMEDADES::neoplasias::neoplasias por localización::neoplasias de la mama Otros calificadores::Otros calificadores::Otros calificadores::/farmacoterapia FENÓMENOS Y PROCESOS::fenómenos fisiológicos::fenómenos farmacológicos y toxicológicos::fenómenos farmacológicos::resistencia a medicamentos::resistencia a los antineoplásicos COMPUESTOS QUÍMICOS Y DROGAS::acciones y usos químicos::acciones farmacológicas::usos terapéuticos::antineoplásicos Otros calificadores::Otros calificadores::/uso terapéutico Cancer therapeutic resistance; Target identification Resistencia terapéutica contra el cáncer; Identificación de objetivos Resistència terapèutica contra el càncer; Identificació d'objectius The PI3K pathway is commonly activated in breast cancer, with PI3K-AKT pathway inhibitors used clinically. However, mechanisms that limit or enhance the therapeutic effects of PI3K-AKT inhibitors are poorly understood at a genome-wide level. Parallel CRISPR screens in 3 PTEN-null breast cancer cell lines identified genes mediating resistance to capivasertib (AKT inhibitor) and AZD8186 (PI3Kβ inhibitor). The dominant mechanism causing resistance is reactivated PI3K-AKT-mTOR signalling, but not other canonical signalling pathways. Deletion of TSC1/2 conferred resistance to PI3Kβi and AKTi through mTORC1. However, deletion of PIK3R2 and INPPL1 drove specific PI3Kβi resistance through AKT. Conversely deletion of PIK3CA, ERBB2, ERBB3 increased PI3Kβi sensitivity while modulation of RRAGC, LAMTOR1, LAMTOR4 increased AKTi sensitivity. Significantly, we found that Mcl-1 loss enhanced response through rapid apoptosis induction with AKTi and PI3Kβi in both sensitive and drug resistant TSC1/2 null cells. The combination effect was BAK but not BAX dependent. The Mcl-1i + PI3Kβ/AKTi combination was effective across a panel of breast cancer cell lines with PIK3CA and PTEN mutations, and delivered increased anti-tumor benefit in vivo. This study demonstrates that different resistance drivers to PI3Kβi and AKTi converge to reactivate PI3K-AKT or mTOR signalling and combined inhibition of Mcl-1 and PI3K-AKT has potential as a treatment strategy for PI3Kβi/AKTi sensitive and resistant breast tumours. This work was funded by the Wellcome Trust (WT206194) to KY and MJG and by AstraZeneca to KY, BRD, STB and JTL. 2022-12-20T11:35:56Z 2022-12-20T11:35:56Z 2022-11-11 info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion Dunn S, Eberlein C, Yu J, Gris-Oliver A, Ong SH, Yelland U, et al. AKT-mTORC1 reactivation is the dominant resistance driver for PI3Kβ/AKT inhibitors in PTEN-null breast cancer and can be overcome by combining with Mcl-1 inhibitors. Oncogene. 2022 Nov 11;41:5046–60. 1476-5594 https://hdl.handle.net/11351/8698 10.1038/s41388-022-02482-9 36241868 000873991500002 http://hdl.handle.net/11351/8698 eng Oncogene;41 https://doi.org/10.1038/s41388-022-02482-9 Attribution 4.0 International http://creativecommons.org/licenses/by/4.0/ info:eu-repo/semantics/openAccess application/pdf Springer Nature Scientia