Enhancer heterogeneity of lung neuroendocrine tumors reveals sensitivity to FGF signaling inhibition

Abstract

Well differentiated low grade lung neuroendocrine tumors (lung carcinoids or LNETs) are histo-pathologically classified as typical and atypical LNETs, but each subtype is still heterogenous both at the molecular level and its clinical manifestation. Therefore, the treatment of patients with LNETs 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 have different clinical courses. The genetic, epigenetic, and developmental programs that drive LNETs remain obscure, limiting our abilities to suggest new biomarkers and drug targets. Here we report for the first time genome-wide profiles of cis-regulatory elements. Analysis of these regulatory landscapes uncovered three regulatory subtypes even within typical LNETs. 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 FGF pathway genes, especially FGFR3. Indeed in-vitro and in-vivo FGF inhibition delays HNF+ LNETs growth, suggesting new therapeutic strategies.