Colorectal neuroendocrine neoplasm organoids reveal the potential therapeutic value of targeting BRAF mutations

Vollständiger Abstract

Worum geht es in dieser Arbeit?

Abstract Background Colorectal neuroendocrine neoplasms (NEN) are a rare entity lacking effective pharmacologic therapies. We aimed to address the paucity of preclinical models for colorectal NEN that facilitate the exploration of novel therapeutic strategies. Methods We used 3-dimensional culture techniques to establish colorectal NEN organoids. These organoids were subjected to pathological examination and sequence analyses to verify their neuroendocrine nature. Subsequently, the organoids were subcutaneously implanted into mice to create patient-derived organoid xenograft (PDOX) models. In vitro and in vivo experiments were conducted to identify potential antitumor strategies. Results We established 3 colorectal NEN organoids, one of which exhibited a BRAF mutation. These organoids closely recapitulated the original tumors in terms of synaptophysin, chromogranin, CD56, somatostatin receptor 2, and Ki-67 expression. DNA- and RNA-sequence analyses confirmed that the organoids preserved the genetic characteristics of their source tumors. In vitro pharmacological assays demonstrated that BRAF inhibitors (IC50: dabrafenib = 3.766 μM; encorafenib = 5.454 μM) and MEK inhibitors (IC50: trametinib = 6.602 nM; binimetinib = 0.749 μM) effectively inhibited the proliferation of organoids harboring the BRAF mutation. The combination of BRAF and MEK inhibitors (IC50: dabrafenib = 0.505 μM, trametinib = 6.395 nM; encorafenib = 1.467 μM, binimetinib = 0.210 μM) exhibited significant enhanced anticancer effects. PDOX experiments revealed that continuous oral administration of dabrafenib and trametinib resulted in a tumor growth inhibition of 66.27%. Conclusion Organoids represent reliable preclinical models for drug screening in colorectal NENs, and BRAF mutations may constitute a promising therapeutic target for patients with colorectal NENs.