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| Ref Type | Journal Article | ||||||||||||
| PMID | (23674493) | ||||||||||||
| Authors | Weigelt B, Warne PH, Lambros MB, Reis-Filho JS, Downward J | ||||||||||||
| Title | PI3K pathway dependencies in endometrioid endometrial cancer cell lines. | ||||||||||||
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| Abstract Text | Endometrioid endometrial cancers (EEC) frequently harbor coexisting mutations in phosphoinositide 3-kinase (PI3K) pathway genes, including PTEN, PIK3CA, PIK3R1, and KRAS. We sought to define the genetic determinants of PI3K pathway inhibitor response in EEC cells, and whether PTEN-mutant EEC cell lines rely on p110β signaling for survival.Twenty-four human EEC cell lines were characterized for their mutation profile and activation state of PI3K and mitogen-activated protein kinase (MAPK) signaling pathway proteins. Cells were treated with pan-class I PI3K, p110α, and p110β isoform-specific, allosteric mTOR, mTOR kinase, dual PI3K/mTOR, mitogen-activated protein/extracellular signal-regulated kinase (MEK), and RAF inhibitors. RNA interference (RNAi) was used to assess effects of KRAS silencing in EEC cells.EEC cell lines harboring PIK3CA and PTEN mutations were selectively sensitive to the pan-class I PI3K inhibitor GDC-0941 and allosteric mTOR inhibitor temsirolimus, respectively. Subsets of EEC cells with concurrent PIK3CA and/or PTEN and KRAS mutations were sensitive to PI3K pathway inhibition, and only 2 of 6 KRAS-mutant cell lines showed response to MEK inhibition. KRAS RNAi silencing did not induce apoptosis in KRAS-mutant EEC cells. PTEN-mutant EEC cell lines were resistant to the p110β inhibitors GSK2636771 and AZD6482, and only in combination with the p110α selective inhibitor A66 was a decrease in cell viability observed.Targeted pan-PI3K and mTOR inhibition in EEC cells may be most effective in PIK3CA- and PTEN-mutant tumors, respectively, even in a subset of EECs concurrently harboring KRAS mutations. Inhibition of p110β alone may not be sufficient to sensitize PTEN-mutant EEC cells and combination with other targeted agents may be required. | ||||||||||||
| Gene Name | Source | Synonyms | Protein Domains | Gene Description | Gene Role |
|---|
| Drug Name | Trade Name | Synonyms | Drug Classes | Drug Description |
|---|---|---|---|---|
| AZD6482 | KIN-193|AZD-6482 | PIK3CB inhibitor 8 PIK3CD inhibitor 27 | AZD6482 inhibits PIK3CB and PIK3CD, preventing the activation of the PI3K signaling pathway and inhibiting tumor cell proliferation, motility, and survival (PMID: 24992874, PMID: 23674493, PMID: 31292159, PMID: 30542720). |
| Gene | Variant | Impact | Protein Effect | Variant Description | Associated with drug Resistance |
|---|
| Molecular Profile | Indication/Tumor Type | Response Type | Therapy Name | Approval Status | Evidence Type | Efficacy Evidence | References |
|---|---|---|---|---|---|---|---|
| PIK3CA mutant | endometrial cancer | sensitive | Pictilisib | Preclinical | Actionable | In a preclinical study, endometrioid endometrial cancer cell lines harboring PIK3CA mutations demonstrated increased sensitivity to GDC-0941 (Pictilisib) induced growth inhibition comparing to PIK3CA wild-type cells in culture (PMID: 23674493). | 23674493 |
| PTEN mutant | endometrial cancer | sensitive | A66 + AZD6482 | Preclinical | Actionable | In a preclinical study, A66 and AZD6482 combination treatment inhibited viability of endometrioid endometrial cancer cell lines harboring PTEN mutations in culture (PMID: 23674493). | 23674493 |
| PTEN mutant | endometrial cancer | resistant | TGX-221 | Preclinical | Actionable | In a preclinical study, endometrioid endometrial cancer cell lines harboring PTEN mutations demonstrated resistance to TGX-221 induced growth inhibition in culture (PMID: 23674493). | 23674493 |
| PTEN mutant | endometrial cancer | resistant | AZD6482 | Preclinical | Actionable | In a preclinical study, endometrioid endometrial cancer cell lines harboring PTEN mutations demonstrated resistance to AZD6482 induced growth inhibition in culture (PMID: 23674493). | 23674493 |
| PTEN loss | prostate cancer | sensitive | GSK2636771 | Preclinical | Actionable | In a preclinical study, GSK2636771 inhibited viability of prostate cancer cell lines harboring PTEN deficiency in culture (PMID: 23674493). | 23674493 |
| PTEN mutant | endometrial cancer | resistant | GSK2636771 | Preclinical | Actionable | In a preclinical study, endometrioid endometrial cancer cell lines harboring PTEN mutations demonstrated resistance to GSK2636771 induced growth inhibition in culture (PMID: 23674493). | 23674493 |
| PTEN loss | breast cancer | sensitive | GSK2636771 | Preclinical | Actionable | In a preclinical study, GSK2636771 inhibited viability of breast cancer cell lines harboring PTEN deficiency in culture (PMID: 23674493). | 23674493 |
| PTEN mutant | endometrial cancer | resistant | A66 | Preclinical | Actionable | In a preclinical study, endometrioid endometrial cancer cell lines harboring PTEN mutations demonstrated resistance to A66 induced growth inhibition in culture (PMID: 23674493). | 23674493 |
| PTEN mutant | endometrial cancer | sensitive | A66 + GSK2636771 | Preclinical | Actionable | In a preclinical study, A66 and GSK2636771 combination treatment inhibited viability of endometrioid endometrial cancer cell lines harboring PTEN mutations in culture (PMID: 23674493). | 23674493 |
| PTEN loss | prostate cancer | sensitive | AZD6482 | Preclinical | Actionable | In a preclinical study, AZD6482 inhibited viability of prostate cancer cell lines harboring PTEN deficiency in culture (PMID: 23674493). | 23674493 |
| PTEN loss | breast cancer | sensitive | AZD6482 | Preclinical | Actionable | In a preclinical study, AZD6482 inhibited viability of breast cancer cell lines harboring PTEN deficiency in culture (PMID: 23674493). | 23674493 |