Summary of project PR002111
This data is available at the NIH Common Fund's National Metabolomics Data Repository (NMDR) website, the Metabolomics Workbench, https://www.metabolomicsworkbench.org, where it has been assigned Project ID PR002111. The data can be accessed directly via it's Project DOI: 10.21228/M8RC0H This work is supported by NIH grant, U2C- DK119886.
See: https://www.metabolomicsworkbench.org/about/howtocite.php
| Project ID: | PR002111 |
| Project DOI: | doi: 10.21228/M8RC0H |
| Project Title: | Inhibition of GPX4 enhances CDK4/6 inhibitor and endocrine therapy activity in breast cancer. |
| Project Type: | MS quantitative analysis |
| Project Summary: | CDK4/6 inhibition in combination with endocrine therapy is the standard of care for estrogen receptor (ER+) breast cancer, and although cytostasis is frequently observed, new treatment strategies that enhance efficacy are required. We performed two independent genome-wide CRISPR screens to identify genetic determinants of CDK4/6 and endocrine therapy sensitivity. Genes involved in oxidative stress and ferroptosis modulated sensitivity, with GPX4 the top sensitiser in both screens. Depletion or inhibition of GPX4 increased sensitivity to palbociclib and giredestrant, and their combination, in ER+ breast cancer models, with GPX4 null xenografts being highly sensitive to palbociclib. GPX4 perturbation additionally sensitised triple negative breast cancer models to palbociclib. Palbociclib and giredestrant induced oxidative stress and disordered lipid metabolism, leading to a ferroptosis-sensitive state. Lipid peroxidation was promoted by a peroxisome AGPAT3-dependent pathway in ER+ breast cancer models, rather than the classical ACSL4 pathway. Our data demonstrate that CDK4/6 and ER inhibition creates vulnerability to ferroptosis induction, that could be exploited through combination with GPX4 inhibitors, to enhance sensitivity to the current therapies in breast cancer. |
| Institute: | Genentech Inc. |
| Last Name: | Wong |
| First Name: | Weng Ruh |
| Address: | 1 DNA Way, South San Francisco, CA 94080, USA |
| Email: | wongw24@gene.com |
| Phone: | 4089048962 |
| Contributors: | Herrera-Abrey MT, Guan J, Khalid U, Ning J, Costa MR, Chan J, Li Q, Fortin J-P, Perampalam P, Biton A, Sandoval W, Vijay J, Hafner M, Cutts R, Wilson G, Frankum J, Roumeliotis TI, Alexander J, Hickman O, Brough R, Haider S, Choudhary J, Lord CJ, Swain, A, Metcalfe C, Tuner NC |
Summary of all studies in project PR002111
| Study ID | Study Title | Species | Institute | Analysis(* : Contains Untargted data) | Release Date | Version | Samples | Download(* : Contains raw data) |
|---|---|---|---|---|---|---|---|---|
| ST003409 | Impact of giredestrant on the lipid profile of MCF-7 breast cancer cells | Homo sapiens | Genentech Inc. | MS | 2024-09-08 | 1 | 28 | Uploaded data (4.9M)* |
| ST003410 | Lipidomics Analysis of ER+ Breast Cancer Cells Treated with Giredestrant and Palbociclib | Homo sapiens | Genentech Inc. | MS | 2024-09-08 | 1 | 32 | Uploaded data (5M)* |
