High-Level Clonal FGFR Amplification and Response to FGFR Inhibition in a Translational Clinical Trial

Abstract

FGFR1 and FGFR2 are amplified in many tumor types, yet what determines response to FGFR inhibition in amplified cancers is unknown. In a translational clinical trial, we show that gastric cancers with high-level clonal FGFR2 amplification have a high response rate to the selective FGFR inhibitor AZD4547, whereas cancers with subclonal or low-level amplification did not respond. Using cell lines and patient-derived xenograft models, we show that high-level FGFR2 amplification initiates a distinct oncogene addiction phenotype, characterized by FGFR2-mediated transactivation of alternative receptor kinases, bringing PI3K/mTOR signaling under FGFR control. Signaling in low-level FGFR1-amplified cancers is more restricted to MAPK signaling, limiting sensitivity to FGFR inhibition. Finally, we show that circulating tumor DNA screening can identify high-level clonally amplified cancers. Our data provide a mechanistic understanding of the distinct pattern of oncogene addiction seen in highly amplified cancers and demonstrate the importance of clonality in predicting response to targeted therapy. Significance Robust single-agent response to FGFR inhibition is seen only in high-level FGFR-amplified cancers, with copy-number level dictating response to FGFR inhibition in vitro, in vivo, and in the clinic. High-level amplification of FGFR2 is relatively rare in gastric and breast cancers, and we show that screening for amplification in circulating tumor DNA may present a viable strategy to screen patients.

Oncogenic Characterization and Pharmacologic Sensitivity of Activating Fibroblast Growth Factor Receptor (FGFR) Genetic Alterations to the Selective FGFR Inhibitor Erdafitinib

“…The discrepancy of the findings may be due to the different methodologies used in the assessment of the FGFR high-level amplifications. The SNU-16 gastric cell line with high-level of FGFR2 amplification has been shown to be sensitive to erdafitinib, which is in concordance with the data reported for AZD4547 (34). However, overexpression of FGFRs in transformation assays is not sufficient to confer a potent oncogenic effect without ligand expression (27), suggesting that FGFR gene amplifications may be less dominant driver pathway events compared with translocations.…”

“…Preclinically, sensitivity was also seen with FGFR amplifications in tumor cell lines and xenograft models, where a decrease in signaling downstream of FGFR was demonstrated upon administration of FGFR inhibitors. A recent report of positive clinical activity of the FGFR inhibitor AZD4547 in gastric and breast cancer patients with high-level amplification of FGFR2 is very encouraging (34). Interestingly, in the current study the high-level amplification of FGFR2 was observed in breast, NSCLC, and ovarian cancers at a frequency of 6.6%, 5.6%, and 6.0%, respectively.…”

Acquired Resistance to FGFR Inhibitor in Diffuse-Type Gastric Cancer through an AKT-Independent PKC-Mediated Phosphorylation of GSK3β

“…Targeting FGFR2 is an attractive therapeutic option for DGC, as FGFR2 amplification is found in approximately 10% of all gastric tumors, and high FGFR2 expression has been correlated with tumor progression and poor survival in DGC (37). A recent clinical trial has demonstrated that gastric cancers with high-level FGFR2 amplification have a high response rate to AZD4547 (15), and several clinical and preclinical studies have also shown that FGFR amplification predicts sensitivity to FGFR inhibitors such as BGJ398 and AZD4547 (38)(39)(40).…”

“…Consequently, deregulation of FGFR signaling through gene amplification, chromosomal translocation, or gain-of-function mutations has been shown to initiate cancer and sustain cancer cell proliferation due to enhanced kinase activity and constitutive activation of downstream targets (14). Recent clinical studies have demonstrated that FGFR-amplified tumors are highly sensitive to FGFR inhibition and therefore susceptible to therapeutic targeting using selective small-molecule FGFR inhibitors such as AZD4547 and BGJ398 (15,16). However, despite initial sensitivity to FGFR inhibitors in the clinic, patients rapidly develop resistance against these agents.…”

Mechanisms of Primary Drug Resistance in FGFR1-Amplified Lung Cancer

“…Additional clinical trials using the FGFR inhibitors, AZD4547 or JNJ-42756493 to treat solid tumors bearing FGFR1, 2, or 3 alterations yielded similar results. All FGFR inhibitors were associated with moderate toxicity including hyperphosphatemia, decreased appetite, constipation, fatigue, dry mouth, and nail toxicity (1, 10,11). Of interest, FGFR2-amplified gastric cancers and FGFR2/3-rearranged urothelial/bladder cancers appear to be the more sensitive to FGFR inhibition.…”