Poster Presentation 28th Lorne Cancer Conference 2016

PI3K inhibitors enhance the efficacy of FGFR inhibitor in FGFR2 mutant endometrial cancers (#150)

Xinyan Geng 1 , Vanessa Bonazzi 1 , Robert Ju 1 , Clare Mahon 1 , Sally-Anne Stephenson 2 , Leisl Packer 1 , Pamela Pollock 1
  1. Endometrial Cancer Laboratory, Chronic Disease and Ageing Theme, Institute of Health & Biomedical Innovation, Queensland University of Technology, QLD, Woolloongabba, QLD, Australia
  2. Eph Receptor Biology Group, Chronic Disease and Ageing Theme, Institute of Health & Biomedical Innovation, Queensland University of Technology, Woolloongabba, QLD, Australia

Patients who present with metastatic endometrial cancer (EC) have only an average of 12 months survival. Somatic FGFR2 mutations have been identified in the tumours from 10-15% of EC patients. Additionally, about 90% of EC patients harbour genetic aberrations in components of the PI3K/AKT pathway leading to constitutive activation. Following FGFR inhibition (FGFRi) in sensitive FGFR2mutant EC cell lines we observe an induction of cell death accompanied by a loss of phospho-ERK with little effect on phospho-AKT levels.  We therefore hypothesized that dual targeting of FGFR2 and the PI3K pathway should lead to an increase in cell death.

Two FGFR2-mutant FGFRi-sensitive EC cell lines (AN3CA and JHUEM2) were treated with the following inhibitors alone or in combination: pan–FGFR inhibitor (BGJ398), pan-PI3K inhibitors (GDC0941 or BKM120), specific PI3Kα inhibitor (BYL719) and MEK inhibitor (Trametinib). We then assessed synergy using the Chou and Talalay methodology, and quantified cell death using Annexin V cell apoptosis and colony formation assays alongside Western blot analysis. The efficacy of BGJ398 and GDC0941 was assessed in vivo in mouse tumour xenograft models.

The combination of BGJ398 with either of the pan-PI3K inhibitors or the specific PI3Kα inhibitor were synergistic in both cell lines. Partial and complete tumour regression of the xenografts was observed in mice treated with BGJ398 + GDC0941 and BGJ398 + BYL719. The combination of Trametinib and GDC0941 resulted in significantly less cell death than the combination of BGJ398 and GDC0941 suggesting that other signalling pathways downstream of FGFR were also involved.  BGJ398 but not Trametinib or GDC0941 can inhibit the activity of PLCγ1 indicating inhibition of this pathway may be involved in cell death induction.

The combination of FGFRi and PI3Ki has a synergistic effect in FGFR2-mutant FGFRi-sensitive EC cells and this combination is anticipated to improved clinical benefit to FGFR2-mutant EC patients by leading to durable tumour regression.

  1. Pollock, P.M., et al., Frequent activating FGFR2 mutations in endometrial carcinomas parallel germline mutations associated with craniosynostosis and skeletal dysplasia syndromes. Oncogene, 2007. 26(50): p. 7158-62
  2. Dutt, A., et al., Drug-sensitive FGFR2 mutations in endometrial carcinoma. Proc Natl Acad Sci U S A, 2008. 105(25): p. 8713-7.
  3. Chou, T.-C. Theoretical basis, experimental design and computerized simulation of synergism and antagonism in drug combination studies. Pharmacol. Rev. 58: 621-681, 2006