Therapeutic Potential for FGFR Inhibitors in SOX9-FGFR2 Coexpressing Pancreatic Cancer

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To the Editor:
Targeting molecular descriptors of pancreatic embryogenesis may be relevant to treating pancreatic ductal adenocarcinoma (PDAC). This strategy recognizes the cancer stem cell hypothesis of multipotential cancer stem cells having limitless replicative potential and multilineage differentiation. This is relevant to postoperative recurrence of occult residual disease. Embryological important pathways are preferentially characteristic of these cells. A relevant descriptor for PDAC is that a SOX9-FGF feed-forward loop maintains pancreatic organ identity in embryogenesis.1 In mice, Sox9, Fgfr2, and Fgf10 form a feed-forward expression loop in the early pancreatic organ niche. Interrupting the SOX9-FGFR2, feed-forward loop by targeting FGFR2 may provide a vicarious means to ablate the effector role of the SOX9 transcription factor in patients with PDAC.
The fibroblast growth factor families of ligand bind to 4 different types of receptors, entitled FGFR1, FGFR2, FGFR3, or FGFR4.2 Alternative gene splicing creates the FGFR2b isoform. The 20 constituent members of the SOX family of gene have homologous DNA binding sequences termed HMG-box. They encode transcription factors, which bind to the DNA minor groove. Their HMG sequences are similar to SRY involved in sex determination. Sox genes have similarity to the Tcf/Lef1 families of genes, which are genes that bind β-catenin, a downstream effector of the Wnt signaling pathway.3 Future synergistic treatment strategies may include combinations of drugs such as AZD-4547 (an inhibitor of FGFR1, FGFR2, and FGFR3; respective IC50, 0.2 nM, 2.5 nM, 1.8 nM) and LGK-974 (which inhibits membrane translocation of Wnt ligand upstream of TCF/LEF). Canonical Wnt signaling is required for pancreatic cancer carcinogenesis.4
Pancreatic ductal adenocarcinoma is not the only tumor type in which the relationship between members of the SOX and FGFR families of genes are of interest. The most significantly amplified genes in squamous cell lung cancer are SOX2 on chromosome 3q26.33 and FGFR1 on chromosome 8p12.5 These amplifications are almost entirely mutually exclusive in squamous cell lung cancer, suggesting an epistatic relationship. SOX2 is one of the 4 “Yamanaka” transcription factors, which can reprogram differentiated cells into induced pluripotential stem cells with inferences for recrudescence of resected disease from occult residual malignant cells.
In St Vincent's University Hospital, Dublin, specimens of patients post pancreaticoduodenectomy with a minimum of 2 years' follow-up were evaluated. We examined immunohistochemistry (IHC) expression of SOX9, FGFR2, and DPC 4 in specimens from 59 patients (R0, n = 55 [93%]; R1, n = 4 [7%]). SOX9-FGFR2 coexpression (SF+) on IHC was correlated with clinicopathological variants only in the R0 subgroup. The mean duration of follow-up was 4.5 years. The pathological tumor axis, the mean number of positive lymph nodes resected, and the mean number of negative lymph nodes resected were among the variables assessed. Staining for SOX9 is illustrated in Figure 1.
A statistically significant correlation of SOX9-FGFR2 coexpression with a greater maximum tumor dimension and median number of positive lymph nodes in resected PDAC was found in the study. It suggests that the SOX9-FGFR2b feed-forward loop has a “lineage dependency” role in PDAC. Amplification of tissue-specific transcription factors in specific cancers had led to the lineage dependency concept with tumor cell progression and survival dependent on pathways that participate in normal development.6 It merits considering if subverting the lineage dependency of PDAC by targeted interruption of the SOX9-FGFR2b feed-forward loop may be therapeutically efficacious. In mice, pancreatic progenitor cell–specific ablation of Sox9 during early organogenesis causes pancreas-to-liver cell fate, therefore subverting the predetermined lineage path.1 FGFR inhibitors such as BGJ-398 are in varying stages of clinical development and may vicariously target the SOX9 transcription factor by effecting feed-forward loop discontinuity.

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