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Ref Type Journal Article
PMID (28119489)
Authors Packer LM, Geng X, Bonazzi VF, Ju RJ, Mahon CE, Cummings MC, Stephenson SA, Pollock PM
Title PI3K Inhibitors Synergize with FGFR Inhibitors to Enhance Antitumor Responses in FGFR2mutant Endometrial Cancers.
Journal Molecular cancer therapeutics
Vol 16
Issue 4
Date 2017 04
URL
Abstract Text Improved therapeutic approaches are needed for the treatment of recurrent and metastatic endometrial cancer. Endometrial cancers display hyperactivation of the MAPK and PI3K pathways, the result of somatic aberrations in genes such as FGFR2, KRAS, PTEN, PIK3CA, and PIK3R1 The FGFR2 and PI3K pathways, have emerged as potential therapeutic targets in endometrial cancer. Activation of the PI3K pathway is seen in more than 90% of FGFR2mutant endometrial cancers. This study aimed to examine the efficacy of the pan-FGFR inhibitor BGJ398 with pan-PI3K inhibitors (GDC-0941, BKM120) and the p110α-selective inhibitor BYL719. We assessed synergy in three FGFR2mutant endometrial cancer cell lines (AN3CA, JHUEM2, and MFE296), and the combination of BGJ398 and GDC-0941 or BYL719 showed strong synergy. A significant increase in cell death and decrease in long-term survival was seen when PI3K inhibitors were combined with BGJ398. Importantly, these effects were seen at low concentrations correlating to only partial inhibition of AKT. The combination of BGJ398 and GDC-0941 showed tumor regressions in vivo, whereas each drug alone only showed moderate tumor growth inhibition. BYL719 alone resulted in increased tumor growth of AN3CA xenografts but in combination with BGJ398 resulted in tumor regression in both AN3CA- and JHUEM2-derived xenografts. These data provide evidence that subtherapeutic doses of PI3K inhibitors enhance the efficacy of anti-FGFR therapies, and a combination therapy may represent a superior therapeutic treatment in patients with FGFR2mutant endometrial cancer. Mol Cancer Ther; 16(4); 637-48. ©2017 AACR.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
PIK3CA E978K missense unknown PIK3CA E978K lies within the PI3K/PI4K domain of the Pik3ca protein (UniProt.org). E978K has been identified in the scientific literature (PMID: 28119489), but has not been biochemically characterized and therefore, its effect on Pik3ca protein function is unknown (PubMed, Mar 2022).
PIK3CA I20M missense unknown PIK3CA I20M lies within the PI3K-ABD domain of the Pik3ca protein (UniProt.org). I20M has been identified in the scientific literature (PMID: 29426295, PMID: 28119489), but has not been biochemically characterized and therefore, its effect on Pik3ca protein function is unknown (PubMed, Mar 2022).
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
FGFR2 N550K PIK3CA I20M PIK3CA P539R PTEN R130Q PTEN T321fs endometrial cancer sensitive Buparlisib + Infigratinib Preclinical - Cell culture Actionable In a preclinical study, the combination of Truseltiq (infigratinib) and Buparlisib (BKM120) resulted in a synergistic effect, demonstrating inhibition of cell proliferation, decreased colony formation, and cell death in an endometrial cancer cell line harboring FGFR2 N550K, PIK3CA I20M and P539R, and PTEN R130Q and T321fs*23 in culture (PMID: 28119489). 28119489
FGFR2 N550K PIK3CA I20M PIK3CA P539R PTEN R130Q PTEN T321fs endometrial cancer sensitive Alpelisib + Infigratinib Preclinical - Cell culture Actionable In a preclinical study, the combination of Truseltiq (infigratinib) and Alpelisib (BYL719) resulted in a synergistic effect, demonstrating inhibition of cell proliferation and induced cell death in an endometrial cancer cell line harboring FGFR2 N550K, PIK3CA I20M and P539R, and PTEN R130Q and T321fs*23 in culture (PMID: 28119489). 28119489
FGFR2 N550K PIK3CA I20M PIK3CA P539R PTEN R130Q PTEN T321fs endometrial cancer sensitive Infigratinib + Pictilisib Preclinical - Cell culture Actionable In a preclinical study, the combination of Truseltiq (infigratinib) and Pictilisib (GDC-0941) resulted in a synergistic effect, demonstrating inhibition of cell proliferation, decreased colony formation, and cell death in an endometrial cancer cell line harboring FGFR2 N550K, PIK3CA I20M and P539R, and PTEN R130Q and T321fs*23 in culture (PMID: 28119489). 28119489