延缓fgfr2抑制剂的耐药

Fgfr2抑制剂有厄达替尼、培米替尼、英菲格拉替尼等常用药；延缓fgfr2抑制剂的耐药可以从抑制egfr、抑制mtor、抑制ros1三个路径着手：


一、抑制egfr

《EGFR Inhibition Potentiates FGFR Inhibitor Therapy and Overcomes Resistance in FGFR2 Fusion-Positive Cholangiocarcinoma》

“We found that feedback activation of EGFR signaling limits FGFR inhibitor efficacy, restricting cell death induction in sensitive models and causing resistance in insensitive models lacking secondary FGFR2 mutations. Inhibition of wild-type EGFR potentiated responses to FGFR inhibitors in both contexts, durably suppressing MEK/ERK and mTOR signaling, increasing apoptosis, and causing marked tumor regressions in vivo. Our findings reveal EGFR-dependent adaptive signaling as an important mechanism limiting FGFR inhibitor efficacy and driving resistance and support clinical testing of FGFR/EGFR inhibitor therapy for FGFR2 fusion-positive cholangiocarcinoma.”

文中所用的egfr抑制剂是 阿法替尼和吉非替尼。


二、抑制mtor

《Efficacy of FGFR Inhibitors and Combination Therapies for Acquired Resistance in FGFR2-Fusion Cholangiocarcinoma》

“we identified upregulation of the PI3K/AKT/mTOR signaling pathway in cells harboring the FGFR2 p.E565A mutation and demonstrated that combination therapy strategies with FGFR and mTOR inhibitors may be used to overcome resistance to FGFR inhibition, specific to infigratinib. Collectively, these studies support the development of novel combination therapeutic strategies in addition to the next generation of FGFR inhibitors to overcome acquired resistance in patients.”

Mtor抑制剂有依维莫司、西罗莫司、白蛋白型西罗莫司等药物。

三、抑制ros1

1、cdh1突变是fgfr2抑制剂耐药的原因之一

《2b or Not 2b: How Opposing FGF Receptor Splice Variants Are Blocking Progress in Precision Oncology》

“The differentiating and regulatory actions of wild-type FGFR2b contrast with the proliferative actions of FGFR1 and FGFR3, and may be converted to mitogenicity either by splice switching or by silencing of tumor suppressor genes such as CDH1 or PTEN. ”

（另外pten失活要用mtor抑制剂，这是呼应了上面一篇论文的结论的）

2、cdh1目前还没有专门的靶向药上市，目前采取的治疗策略是抑制ros1合成致死

《E-Cadherin/ROS1 Inhibitor Synthetic Lethality in Breast Cancer》

“The cell adhesion glycoprotein E-cadherin (CDH1) is commonly inactivated in breast tumors. Precision medicine approaches that exploit this characteristic are not available. Using perturbation screens in breast tumor cells with CRISPR/Cas9-engineered CDH1 mutations, we identified synthetic lethality between E-cadherin deficiency and inhibition of the tyrosine kinase ROS1. Data from large-scale genetic screens in molecularly diverse breast tumor cell lines established that the E-cadherin/ROS1 synthetic lethality was not only robust in the face of considerable molecular heterogeneity but was also elicited with clinical ROS1 inhibitors, including foretinib and crizotinib. ROS1 inhibitors induced mitotic abnormalities and multinucleation in E-cadherin-defective cells, phenotypes associated with a defect in cytokinesis and aberrant p120 catenin phosphorylation and localization. In vivo, ROS1 inhibitors produced profound antitumor effects in multiple models of E-cadherin-defective breast cancer. These data therefore provide the preclinical rationale for assessing ROS1 inhibitors, such as the licensed drug crizotinib, in appropriately stratified patients”

Cdh1是编码E-Cadherin蛋白的。用ros1抑制剂克唑替尼治疗chd1突变的乳腺癌、胃癌的临床试验目前正在进行中。
NCT03620643：《Crizotinib in Lobular Breast, Diffuse Gastric and Triple Negative Lobular Breast Cancer or CDH1-mutated Solid Tumours (ROLo)》