Acquired resistance to BRAF inhibitors is mediated by BRAF splicing variants in BRAF V600E mutation-positive colorectal neuroendocrine carcinoma. (1st September 2022)

• Record Type: Journal Article
• Authors: Shimizu, Yuki; Maruyama, Kohei; Suzuki, Mai; Kawachi, Hiroshi; Low, Siew-Kee; Oh-hara, Tomoko; Takeuchi, Kengo; Fujita, Naoya; Nagayama, Satoshi; Katayama, Ryohei
• Is Part Of: Cancer letters. Volume 543(2022)
• Publication Date: 2022-09-01
• Subjects: BRAF -- Neuroendocrine carcinoma -- Colorectal cancer -- Drug resistance -- Splicing variants; CRCs Colorectal cancers -- CRC-NECs Colorectal neuroendocrine carcinomas -- EGFR Epidermal growth factor receptor -- MAPK Mitogen-activated protein kinase -- NECs Neuroendocrine carcinomas -- NSCLC Non-small cell lung cancer -- NENs Neuroendocrine neoplasms -- PDCs Patient-derived cells; Cancer -- Periodicals; Neoplasms -- Periodicals; Cancer -- Périodiques; Electronic journals; 616.994
• DOI: 10.1016/j.canlet.2022.215799
• Languages: English
• ISSNs: 0304-3835

Abstract

Abstract: Neuroendocrine carcinomas (NECs), a poorly differentiated subtype of neuroendocrine neoplasms, are aggressive and have a poor prognosis. Colorectal neuroendocrine carcinomas (CRC-NECs) are observed in about 0.6% of all patients with CRC. Interestingly, patients with CRC-NECs show higher frequencies of BRAF mutation than typical CRC. BRAF V600E mutation-positive CRC-NECs were shown to be sensitive to BRAF inhibitors and now are treated by BRAF inhibitors. Similar to the other BRAF V600E mutated cancers, resistances against BRAF inhibitors have been observed, but the resistance mechanisms are still unclear. In this study, we established BRAF V600E mutated CRC-NEC cell line directly from surgical specimens and experimentally obtained BRAF inhibitor dabrafenib resistant cell lines. The resistant cells are revealed to express at least three types of BRAF splicing variants harboring V600E-mutation, and contribute to RAF/MEK/ERK pathway activation. In these cells, MEK and ERK inhibitors but not dabrafenib significantly suppressed cell growth and survival. Thus, in BRAF V600E mutation-positive CRC-NECs, BRAF splicing variants activate the RAF/MEK/ERK pathway and contribute to acquire BRAF inhibitor resistance. Hence, MEK or ERK are potential therapeutic targets to overcome BRAF resistance. Highlights: BRAF inhibitor resistant CRC-NEC cell line was established from patient derived cells. BRAF splicing variants were found in the BRAF inhibitor resistant CRC-NEC cells. MEK or ERK inhibitor can overcome the BRAF splicing variant mediated resistance.