Reference Detail

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	Vol	Issue	Date	Pages	Journal Short Title
Molecular cancer therapeutics	16	4	2017 04	637-648	Mol Cancer Ther

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.

Filtering

Case insensitive filtering will display rows if any text in any cell matches the filter term
Use simple literal full or partial string matches
Separate multiple filter terms with a space. Any order may be used (i. e. a b c and c b a are equivalent )
Filtering will only apply to rows that are already loaded on the page. Filtering has no impact on query parameters.
Use quotes to match on a longer phrase with spaces (i.e. "mtor c1483f")

Sorting

Generally, the default sort order for tables is set to be first column ascending; however, specific tables may set a different default sort order.
Click on any column header arrows to sort by that column
Hold down the Shift key and click multiple columns to sort by more than one column. Be sure to set ascending or descending order for a given column before moving on to the next column.

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 2024).
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, May 2024).

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	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
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