Abstract C37: Molecular determinants of sensitivity and resistance to FGFR inhibition in FGFR2-amplified gastric cancer
Authors: Babina Irina , Pearson Alex , Cutts Ros , Smyth Elizabeth , Ning Jian , Swain Amanda , Cunningham David , Turner Nicholas C. 
Published: May 2016

Despite improvements in diagnostics and chemotherapy regiments in gastric cancer, there is still an urgent need for novel biomarkers and second-line treatment interventions. High level FGFR2 amplification is found in ∼5% gastric cancers, and responses in FGFR2-amplified gastric cancer have been observed in a phase II study of FGFR inhibitor AZD4547 (Smyth et al ASCO 2015, NCT01795768). Here we studied tumor progression biopsies and patient-derived xenografts (PDX) to understand the mechanisms of sensitivity and resistance in FGFR2-amplified gastric cancer.

PDX models were generated from the baseline biopsies of two Caucasian patients with junctional FGFR2-amplified tumors who had durable responses to AZD4547 in the clinic. Both PDX recapitulated the histology of the original cancers, and whole exome sequencing demonstrated 85-90% agreement mutations between the patient biopsies and the PDX tumors. Similar to the patients, both models were highly sensitive to AZD4547, with regression of ∼60% seen after 10 days treatment, with subsequent stability on chronic dosing.

To understand the molecular mechanisms of sensitivity to AZD4547, we profiled PDX tumors and PDX-derived spheroid cultures with phospho-RTK signaling arrays and by western blot. Although FGFR inhibition resulted in short-term suppression of PI3K-mTOR signaling, chronic exposure resulted in an increase in phospho-S6 and phospho-4EBP1 after 24 hours of treatment. Combination of AZD4547 and the catalytic mTOR inhibitor AZD2014 elicited a greater response in vitro than either drug alone. To examine adaptive response to AZD4547 we excised residual PDX tumors after 60 days treatment, demonstrating upregulated ERBB3 and insulin receptor phosphorylation in tumors adapted to long-term FGFR inhibition. A treatment break, which resumed tumor growth, re-sensitized to AZD4547, suggesting that ongoing FGFR inhibition was required to maintain the adaptive response.

Finally we examined the mechanism of acquired resistance to AZD4547. Two responding patients had progression biopsies. Paired exome sequencing demonstrated an acquired KRAS amplification in one patient, though no evident onco-mutation was identified in patient two. In parallel, long-term treatment of PDX with AZD4547 gave rise to resistant PDX tumors, the results of which will be presented at the conference.

In conclusion, we show that reactivation of mTOR signaling limits sensitivity of FGFR2-amplified tumors to AZD4547, identifying potential combination strategies to deepen response. Studies of acquired resistance are ongoing, with preliminary evidence suggesting acquisition of downstream genetic events.

Citation Format: Irina Babina, Alex Pearson, Ros Cutts, Elizabeth Smyth, Jian Ning, Amanda Swain, David Cunningham, Nicholas C. Turner. Molecular determinants of sensitivity and resistance to FGFR inhibition in FGFR2-amplified gastric cancer. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr C37.