ArticleOncogene2022
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.
Article in Oncogene, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to trial NCT07486648 (The Safety and Efficacy of Osimertinib Plus Capivasertib in EGFRm Advanced Non-small Cell Lung Cancer), which is not on this map. Cited by 26 papers.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
The Safety and Efficacy of Osimertinib Plus Capivasertib in EGFRm Advanced Non-small Cell Lung Cancer (NSCLC) Participants With PIK3CA/AKT1/PTEN Alterations Who Had Progressed on First-line Osimertinib Monotherapy or Plus Chemotherapy: a First-in-human, Phase Ib/Ⅱa Study (PRECISION)
Who cites it
26 citing papers in PubMed, 30 citations in OpenAlex.
- Targeting the Chromatin-Modifying Enzyme, KDM5C, Enhances AKT Inhibition Response in ER+ Breast Cancer.Molecular cancer therapeutics · 2026Article
- lncRNA JPX promotes radioresistance in nasopharyngeal carcinoma via the miR-1301-3p/PIK3R2-mediated autophagy pathway.Translational cancer research · 2026Article
- Capivasertib Combines with Trastuzumab Deruxtecan to Enhance Antitumor Activity in HER2-Positive and HER2-Low Tumors.Molecular cancer therapeutics · 2026Article
- Drugging non-canonical kinases in cancer therapeutics: Molecular targets, underlying mechanisms and small-molecule inhibitors.Acta pharmaceutica Sinica. B · 2026Review
- The anticancer effects of PCAIs in pancreatic cancer cells involve MAPK and PI3K/AKT pathways hyperactivation.Oncotarget · 2026Article
- Developing therapeutic strategies to target MCL1 and BCLXL in lethal prostate cancer.iScience · 2025Article
- Next-generation sequencing methodologies to identify patients for targeted therapy: focus on HR+/HER2- metastatic breast cancer.Pathologica · 2025Review
- Organoid-based two-step drug screening for rapid identification of chemotherapy-resistant oesophageal squamous cell carcinoma and alternative therapies.Clinical and translational medicine · 2025Article
- Elucidating molecularly stratified single agent, and combination, therapeutic strategies targeting MCL1 for lethal prostate cancer.Nature communications · 2025Article
- Polo-like kinase 1 inactivation enhances PI3K inhibition-mediated apoptosis of NOTCH1-mutant head and neck squamous cell carcinoma.Cancer letters · 2025Article
- CRISPR screening approaches in breast cancer research.Cancer metastasis reviews · 2025Review
- Emerging Mechanisms of Therapy Resistance in Metastatic ER+ Breast Cancer.Endocrinology · 2025Review
- Article
- Review
- The interplay between FOXO3 and FOXM1 influences sensitivity to AKT inhibition in PIK3CA and PIK3CA/PTEN altered estrogen receptor positive breast cancer.NPJ breast cancer · 2025Article
- A Promising Resveratrol Analogue Suppresses CSCs in Non-Small-Cell Lung Cancer via Inhibition of the ErbB2 Signaling Pathway.Chemical research in toxicology · 2025Article
- Molecular biology of the novel anticancer medications: a focus on kinases inhibitors, biologics and CAR T-cell therapy.Inflammation research : official journal of the European Histamine Research Society ... [et al.] · 2025Review
- Use of metabolic imaging to monitor heterogeneity of tumour response following therapeutic mTORC1/2 pathway inhibition.Disease models & mechanisms · 2025Article
- Potent combination benefit of the AKT inhibitor capivasertib and the BCL-2 inhibitor venetoclax in diffuse large B cell lymphoma.Leukemia · 2024Article
- AKT kinases as therapeutic targets.Journal of experimental & clinical cancer research : CR · 2024Review
Corrections and comments
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Authors and funding
21 authors at 5 institutions in 5 countries.
Funding
Abstract
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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.