Enhancer heterogeneity of lung carcinoids reveals sensitivity to FGF signaling inhibition (A06)

Introduction: Well-differentiated low grade lung carcinoids are histo-pathologically classified as typical and atypical, but each subtype is still heterogenous both at the molecular level and its clinical manifestation. Therefore, the treatment of these patients is challenging. The two main challenges are the lack of effective drug treatments and the lack of reliable biomarkers to guide management since the disease in patients with the same tumor grade/stage often has different clinical courses. The genetic, epigenetic, and developmental programs that drive lung carcinoids remain obscure, limiting our abilities to suggest new biomarkers and drug targets.

Aim(s): Systematic characterization of cis-regulatory elements and transcription in typical and atypical lung carcinoids, and validation of candidate inhibitors in-vitro and in-vivo.

Materials and methods: We profiled for the first time genome-wide maps of cis-regulatory elements of primary lung carcinoids by H3K27ac ChIP-seq and RNA-seq. We tested CDK7/9 or FGF inhibition in cell lines and in a mouse xenograft model.

Results: Analysis of these regulatory landscapes uncovered three regulatory subtypes even within typical lung carcinoids. Comparing enhancer acetylation across subtypes revealed different differentiation signals, one driven by ASCL1, SOX4 and BARX1 factors invoking neuronal-like signature and one driven by HNF1 and HNF4 factors. The HNF+ subtype demonstrated strong enhancers near FGF signaling genes, and differential expression of these genes, especially FGFR3. Indeed in-vitro and in-vivo FGF inhibition delays HNF+ LNETs growth, suggesting new possible therapeutic strategies.

Conclusion: Enhancer profiling helps uncover molecular underpinning of lung carcinoids subtypes and sensitivity of one subtype to FGF inhibition.

Keywords: fgf signaling, lung carcinoids, enhancers