Ladaika Christopher A, Chakraborty Averi, Masood Ashiq, Hostetter Galen, Yi Joo Mi, O'Hagan Heather M
Genome, Cell, and Developmental Biology Graduate Program, Department of Biology, Indiana University Bloomington, Bloomington, IN, 47405, USA.
Medical Sciences Program, Indiana University School of Medicine, Bloomington, IN, 47405, USA.
Mol Cancer. 2025 Apr 23;24(1):122. doi: 10.1186/s12943-025-02311-z.
BRAF activating mutations occur in approximately 10% of metastatic colorectal cancer (CRCs) and are associated with worse prognosis in part due to an inferior response to standard chemotherapy. Standard of care for patients with refractory metastatic BRAF CRC is treatment with BRAF and EGFR inhibitors and recent FDA approval was given to use these inhibitors in combination with chemotherapy for patients with treatment naïve metastatic BRAF CRC. Lineage plasticity to neuroendocrine cancer is an emerging mechanism of targeted therapy resistance in several cancer types. Enteroendocrine cells (EECs), the neuroendocrine cell of the intestine, are uniquely present in BRAF mutant CRC as compared to BRAF wildtype CRC.
BRAF plus EGFR inhibitor treatment induced changes in cell composition were determined by gene expression, imaging and single cell approaches in multiple models of BRAF mutant CRC. Furthermore, multiple clinically relevant inhibitors of the lysine demethylase LSD1 were tested to determine which inhibitor blocked the changes in cell composition.
Combined BRAF and EGFR inhibition enriched for EECs in all BRAF mutant CRC models tested. Additionally, EECs and other secretory cell types were enriched in a subset of BRAF CRC patient samples following targeted therapy. Importantly, inhibition of LSD1 with a clinically relevant inhibitor attenuated targeted therapy-induced EEC enrichment through blocking the interaction of LSD1, CoREST2 and STAT3.
Our findings that BRAF plus EGFR inhibition induces lineage plasticity in BRAF CRC represents a new paradigm for how resistance to BRAF plus EGFR inhibition occurs. Additionally, our finding that LSD1 inhibition blocks lineage plasticity has the potential to improve responses to BRAF plus EGFR inhibitor therapy in patients.
BRAF激活突变发生在约10%的转移性结直肠癌（CRC）中，部分由于对标准化疗反应较差，与预后较差相关。难治性转移性BRAF CRC患者的标准治疗是使用BRAF和EGFR抑制剂，最近美国食品药品监督管理局（FDA）批准将这些抑制剂与化疗联合用于初治转移性BRAF CRC患者。向神经内分泌癌的谱系可塑性是几种癌症类型中靶向治疗耐药的一种新兴机制。与BRAF野生型CRC相比，肠内分泌细胞（EEC），即肠道的神经内分泌细胞，在BRAF突变CRC中独特存在。
在多个BRAF突变CRC模型中，通过基因表达、成像和单细胞方法确定BRAF加EGFR抑制剂治疗诱导的细胞组成变化。此外，测试了赖氨酸去甲基化酶LSD1的多种临床相关抑制剂，以确定哪种抑制剂能阻断细胞组成的变化。
在所有测试的BRAF突变CRC模型中，联合BRAF和EGFR抑制使EEC富集。此外，在靶向治疗后的一部分BRAF CRC患者样本中，EEC和其他分泌细胞类型也富集。重要的是，用临床相关抑制剂抑制LSD1可通过阻断LSD1、CoREST2和STAT3的相互作用来减弱靶向治疗诱导的EEC富集。
我们的研究结果表明，BRAF加EGFR抑制在BRAF CRC中诱导谱系可塑性，这代表了对BRAF加EGFR抑制产生耐药的一种新范式。此外，我们发现抑制LSD1可阻断谱系可塑性，这有可能改善患者对BRAF加EGFR抑制剂治疗的反应。
