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PIK3CA and AKT1 mutations have distinct effects on sensitivity to targeted pathway inhibitors in an isogenic luminal breast cancer model system.
| Content Provider | Semantic Scholar |
|---|---|
| Author | Beaver, Julia A. Gustin, John Paul Yi, Kyung Hee Rajpurohit, Anandita K. Thomas, Matthew Gilbert, Samuel F. Rosen, David Marc Park, Ben Ho Lauring, Josh D. |
| Copyright Year | 2013 |
| Abstract | PURPOSE Activating mutations in the phosphoinositide-3-kinase (PI3K)/AKT/mTOR pathway are present in the majority of breast cancers and therefore are a major focus of drug development and clinical trials. Pathway mutations have been proposed as predictive biomarkers for efficacy of PI3K-targeted therapies. However, the precise contribution of distinct PI3K pathway mutations to drug sensitivity is unknown. EXPERIMENTAL DESIGN We describe the creation of a physiologic human luminal breast cancer cell line model to study the phenotype of these mutations using the MCF-7 cell line. We used somatic cell gene targeting to "correct" PIK3CA E545K-mutant alleles in MCF-7 cells to wild-type sequence. The AKT1 E17K hotspot mutation was knocked in on this wild-type background. RESULTS Loss of mutant PIK3CA dramatically reduced phosphorylation of AKT proteins and several known AKT targets, but other AKT target proteins and downstream effectors of mTOR were not affected. PIK3CA wild-type cells exhibited reduced proliferation in vitro and in vivo. Knockin of the AKT1 E17K hotspot mutation on this PIK3CA wild-type background restored pathway signaling, proliferation, and tumor growth in vivo. PIK3CA, but not AKT1 mutation, increased sensitivity to the PI3K inhibitor GDC-0941 and the allosteric AKT inhibitor MK-2206. CONCLUSIONS AKT1 E17K is a bona fide oncogene in a human luminal breast cancer context. Distinct PI3K pathway mutations confer differential sensitivity to drugs targeting the pathway at different points and by distinct mechanisms. These findings have implications for the use of tumor genome sequencing to assign patients to targeted therapies. |
| Starting Page | 37 |
| Ending Page | 54 |
| Page Count | 18 |
| File Format | PDF HTM / HTML |
| Alternate Webpage(s) | http://clincancerres.aacrjournals.org/content/clincanres/early/2013/07/25/1078-0432.CCR-13-0884.full.pdf |
| Alternate Webpage(s) | http://file2.selleckchem.com/citations/MK-2206-GDC-0941-NVP-BEZ235-20130725.pdf |
| Alternate Webpage(s) | http://clincancerres.aacrjournals.org/content/clincanres/19/19/5413.full.pdf |
| PubMed reference number | 23888070v1 |
| Alternate Webpage(s) | https://doi.org/10.1158/1078-0432.CCR-13-0884 |
| DOI | 10.1158/1078-0432.ccr-13-0884 |
| Journal | Clinical cancer research : an official journal of the American Association for Cancer Research |
| Volume Number | 19 |
| Issue Number | 19 |
| Language | English |
| Access Restriction | Open |
| Subject Keyword | 1-Phosphatidylinositol 3-Kinase Biological Markers Breast Cancer Cell Diploid Cell Drug Delivery Systems FRAP1 protein, human GDC 0941 Gene Targeting Genetic Hotspot MK 2206 Malignant neoplasm of breast Mammary Neoplasms Mutation Oncogenes PIK3CA gene PIK3CA protein, human Patients Phenobarbital Proto-Oncogene Proteins c-akt RAC-Alpha Serine/Threonine Kinase Therapeutic procedure drug development |
| Content Type | Text |
| Resource Type | Article |
