Matches in SemOpenAlex for { <https://semopenalex.org/work/W3134079690> ?p ?o ?g. }
- W3134079690 endingPage "2480" @default.
- W3134079690 startingPage "2470" @default.
- W3134079690 abstract "PI3Kα inhibitors have shown clinical activity in PIK3CA-mutated estrogen receptor-positive (ER+) patients with breast cancer. Using whole genome CRISPR/Cas9 sgRNA knockout screens, we identified and validated several negative regulators of mTORC1 whose loss confers resistance to PI3Kα inhibition. Among the top candidates were TSC1, TSC2, TBC1D7, AKT1S1, STK11, MARK2, PDE7A, DEPDC5, NPRL2, NPRL3, C12orf66, SZT2, and ITFG2. Loss of these genes invariably results in sustained mTOR signaling under pharmacologic inhibition of the PI3K-AKT pathway. Moreover, resistance could be prevented or overcome by mTOR inhibition, confirming the causative role of sustained mTOR activity in limiting the sensitivity to PI3Kα inhibition. Cumulatively, genomic alterations affecting these genes are identified in about 15% of PIK3CA-mutated breast tumors and appear to be mutually exclusive. This study improves our understanding of the role of mTOR signaling restoration in leading to resistance to PI3Kα inhibition and proposes therapeutic strategies to prevent or revert this resistance. SIGNIFICANCE: These findings show that genetic lesions of multiple negative regulators of mTORC1 could limit the efficacy of PI3Kα inhibitors in breast cancer, which may guide patient selection strategies for future clinical trials." @default.
- W3134079690 created "2021-03-15" @default.
- W3134079690 creator A5000951196 @default.
- W3134079690 creator A5001090073 @default.
- W3134079690 creator A5001814176 @default.
- W3134079690 creator A5002819777 @default.
- W3134079690 creator A5014140313 @default.
- W3134079690 creator A5014529694 @default.
- W3134079690 creator A5016439377 @default.
- W3134079690 creator A5026467729 @default.
- W3134079690 creator A5026491410 @default.
- W3134079690 creator A5027332245 @default.
- W3134079690 creator A5029733167 @default.
- W3134079690 creator A5032595855 @default.
- W3134079690 creator A5041961484 @default.
- W3134079690 creator A5042743608 @default.
- W3134079690 creator A5054885628 @default.
- W3134079690 creator A5076243488 @default.
- W3134079690 creator A5077235697 @default.
- W3134079690 creator A5077626457 @default.
- W3134079690 creator A5083678360 @default.
- W3134079690 creator A5084753857 @default.
- W3134079690 creator A5089114288 @default.
- W3134079690 date "2021-03-08" @default.
- W3134079690 modified "2023-10-05" @default.
- W3134079690 title "Genomic Alterations in <i>PIK3CA</i>-Mutated Breast Cancer Result in mTORC1 Activation and Limit the Sensitivity to PI3Kα Inhibitors" @default.
- W3134079690 cites W1985754630 @default.
- W3134079690 cites W1988303870 @default.
- W3134079690 cites W1992257057 @default.
- W3134079690 cites W2009886463 @default.
- W3134079690 cites W2025176940 @default.
- W3134079690 cites W2035452022 @default.
- W3134079690 cites W2056137479 @default.
- W3134079690 cites W2057366353 @default.
- W3134079690 cites W2066659565 @default.
- W3134079690 cites W2071463092 @default.
- W3134079690 cites W2082853003 @default.
- W3134079690 cites W2094399892 @default.
- W3134079690 cites W2094517081 @default.
- W3134079690 cites W2099019742 @default.
- W3134079690 cites W2102004296 @default.
- W3134079690 cites W2108360575 @default.
- W3134079690 cites W2111352469 @default.
- W3134079690 cites W2114843025 @default.
- W3134079690 cites W2126783165 @default.
- W3134079690 cites W2136676465 @default.
- W3134079690 cites W2138044466 @default.
- W3134079690 cites W2138319716 @default.
- W3134079690 cites W2149441684 @default.
- W3134079690 cites W2150595264 @default.
- W3134079690 cites W2153096480 @default.
- W3134079690 cites W2167188058 @default.
- W3134079690 cites W223909586 @default.
- W3134079690 cites W2334089645 @default.
- W3134079690 cites W2343358448 @default.
- W3134079690 cites W2506550081 @default.
- W3134079690 cites W2509236360 @default.
- W3134079690 cites W2588791993 @default.
- W3134079690 cites W2588948554 @default.
- W3134079690 cites W2592761229 @default.
- W3134079690 cites W2601176113 @default.
- W3134079690 cites W2613362156 @default.
- W3134079690 cites W2739301023 @default.
- W3134079690 cites W2744377419 @default.
- W3134079690 cites W2773354488 @default.
- W3134079690 cites W2789281724 @default.
- W3134079690 cites W2803254364 @default.
- W3134079690 cites W2891700678 @default.
- W3134079690 cites W2904293303 @default.
- W3134079690 cites W2945564879 @default.
- W3134079690 cites W2946317931 @default.
- W3134079690 cites W2962684613 @default.
- W3134079690 cites W2965244954 @default.
- W3134079690 cites W2982189058 @default.
- W3134079690 cites W2982786587 @default.
- W3134079690 cites W3012647537 @default.
- W3134079690 doi "https://doi.org/10.1158/0008-5472.can-20-3232" @default.
- W3134079690 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/8137641" @default.
- W3134079690 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/33685991" @default.
- W3134079690 hasPublicationYear "2021" @default.
- W3134079690 type Work @default.
- W3134079690 sameAs 3134079690 @default.
- W3134079690 citedByCount "17" @default.
- W3134079690 countsByYear W31340796902021 @default.
- W3134079690 countsByYear W31340796902022 @default.
- W3134079690 countsByYear W31340796902023 @default.
- W3134079690 crossrefType "journal-article" @default.
- W3134079690 hasAuthorship W3134079690A5000951196 @default.
- W3134079690 hasAuthorship W3134079690A5001090073 @default.
- W3134079690 hasAuthorship W3134079690A5001814176 @default.
- W3134079690 hasAuthorship W3134079690A5002819777 @default.
- W3134079690 hasAuthorship W3134079690A5014140313 @default.
- W3134079690 hasAuthorship W3134079690A5014529694 @default.
- W3134079690 hasAuthorship W3134079690A5016439377 @default.
- W3134079690 hasAuthorship W3134079690A5026467729 @default.
- W3134079690 hasAuthorship W3134079690A5026491410 @default.
- W3134079690 hasAuthorship W3134079690A5027332245 @default.
- W3134079690 hasAuthorship W3134079690A5029733167 @default.