Ladaika Christopher A, Chakraborty Averi, Masood Ashiq, Hostetter Galen, Yi Joo Mi, O'Hagan Heather M
bioRxiv. 2024 Oct 29:2024.10.25.620306. doi: 10.1101/2024.10.25.620306.
activating mutations occur in approximately 10% of metastatic colorectal cancer (CRCs) and are associated with worse prognosis due to an inferior response to standard chemotherapy. Standard of care for patients with refractory metastatic CRC is treatment with BRAF and EGFR inhibitors. However, responses are not durable. 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 CRC as compared to wildtype CRC. Here, we demonstrated that combined BRAF and EGFR inhibition enriches for EECs in several models of CRC. Additionally, EECs and other secretory cell types were enriched in a subset of CRC patient samples following targeted therapy. Importantly, inhibition of the lysine demethylase 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 CRC represents a new paradigm for how resistance to BRAF plus EGFR inhibition occurs and our finding that LSD1 inhibition blocks lineage plasticity has the potential to improve responses to BRAF plus EGFR inhibitor therapy in patients.
激活突变约发生在10%的转移性结直肠癌（CRC）中，由于对标准化疗反应较差，与预后不良相关。难治性转移性CRC患者的标准治疗是使用BRAF和EGFR抑制剂。然而，反应并不持久。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性的一种新出现机制。肠内分泌细胞（EEC）是肠道的神经内分泌细胞，与野生型CRC相比，在CRC中独特存在。在这里，我们证明在几种CRC模型中，联合抑制BRAF和EGFR可使EEC富集。此外，在靶向治疗后的一部分CRC患者样本中，EEC和其他分泌细胞类型也有所富集。重要的是，用一种临床相关抑制剂抑制赖氨酸去甲基化酶LSD1，通过阻断LSD1、CoREST2和STAT3之间的相互作用，减弱了靶向治疗诱导的EEC富集。
我们发现BRAF加EGFR抑制在CRC中诱导谱系可塑性，这代表了BRAF加EGFR抑制耐药发生方式的一种新范式，并且我们发现LSD1抑制可阻断谱系可塑性，这有可能改善患者对BRAF加EGFR抑制剂治疗的反应。
