DiPeri Timothy P, Zhao Ming, Evans Kurt W, Varadarajan Kaushik, Moss Tyler, Scott Stephen, Kahle Michael P, Byrnes Charnel C, Chen Huiqin, Lee Sunyoung S, Halim Abdel-Baset, Hirai Hiroshi, Wacheck Volker, Kwong Lawrence N, Rodon Jordi, Javle Milind, Meric-Bernstam Funda
Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston TX, United States.
Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston TX, United States.
J Hepatol. 2024 Feb;80(2):322-334. doi: 10.1016/j.jhep.2023.10.041. Epub 2023 Nov 14.
BACKGROUND & AIMS: There is a knowledge gap in understanding mechanisms of resistance to fibroblast growth factor receptor (FGFR) inhibitors (FGFRi) and a need for novel therapeutic strategies to overcome it. We investigated mechanisms of acquired resistance to FGFRi in patients with FGFR2-fusion-positive cholangiocarcinoma (CCA).
A retrospective analysis of patients who received FGFRi therapy and underwent tumor and/or cell-free DNA analysis, before and after treatment, was performed. Longitudinal circulating tumor DNA samples from a cohort of patients in the phase I trial of futibatinib (NCT02052778) were assessed. FGFR2-BICC1 fusion cell lines were developed and secondary acquired resistance mutations in the mitogen-activated protein kinase (MAPK) pathway were introduced to assess their effect on sensitivity to FGFRi in vitro.
On retrospective analysis of 17 patients with repeat sequencing following FGFRi treatment, new FGFR2 mutations were detected in 11 (64.7%) and new alterations in MAPK pathway genes in nine (52.9%) patients, with seven (41.2%) patients developing new alterations in both the FGFR2 and MAPK pathways. In serially collected plasma samples, a patient treated with an irreversible FGFRi tested positive for previously undetected BRAF V600E, NRAS Q61K, NRAS G12C, NRAS G13D and KRAS G12K mutations upon progression. Introduction of a FGFR2-BICC1 fusion into biliary tract cells in vitro sensitized the cells to FGFRi, while concomitant KRAS G12D or BRAF V600E conferred resistance. MEK inhibition was synergistic with FGFRi in vitro. In an in vivo animal model, the combination had antitumor activity in FGFR2 fusions but was not able to overcome KRAS-mediated FGFRi resistance.
These findings suggest convergent genomic evolution in the MAPK pathway may be a potential mechanism of acquired resistance to FGFRi.
NCT02052778.
We evaluated tumors and plasma from patients who previously received inhibitors of fibroblast growth factor receptor (FGFR), an important receptor that plays a role in cancer cell growth, especially in tumors with abnormalities in this gene, such as FGFR fusions, where the FGFR gene is fused to another gene, leading to activation of cancer cell growth. We found that patients treated with FGFR inhibitors may develop mutations in other genes such as KRAS, and this can confer resistance to FGFR inhibitors. These findings have several implications for patients with FGFR2 fusion-positive tumors and provide mechanistic insight into emerging MAPK pathway alterations which may serve as a therapeutic vulnerability in the setting of acquired resistance to FGFRi.
在理解成纤维细胞生长因子受体（FGFR）抑制剂（FGFRi）的耐药机制方面存在知识空白，因此需要新的治疗策略来克服这一问题。我们研究了FGFR2融合阳性胆管癌（CCA）患者对FGFRi获得性耐药的机制。
对接受FGFRi治疗并在治疗前后进行肿瘤和/或游离DNA分析的患者进行回顾性分析。评估了来自futibatinib一期试验队列（NCT02052778）患者的纵向循环肿瘤DNA样本。构建了FGFR2-BICC1融合细胞系，并引入丝裂原活化蛋白激酶（MAPK）途径中的继发性获得性耐药突变，以评估其对FGFRi体外敏感性的影响。
对17例接受FGFRi治疗后进行重复测序的患者进行回顾性分析，发现11例（64.7%）有新的FGFR2突变，9例（52.9%）患者的MAPK途径基因有新改变，7例（41.2%）患者在FGFR2和MAPK途径均有新改变。在连续采集的血浆样本中，一名接受不可逆FGFRi治疗的患者在疾病进展时检测到先前未检测到的BRAF V600E、NRAS Q61K、NRAS G12C、NRAS G13D和KRAS G12K突变呈阳性。在体外将FGFR2-BICC1融合导入胆管细胞可使细胞对FGFRi敏感，而同时存在KRAS G12D或BRAF V600E则会导致耐药。MEK抑制在体外与FGFRi具有协同作用。在体内动物模型中，该联合方案对FGFR2融合具有抗肿瘤活性，但无法克服KRAS介导的FGFRi耐药。
这些发现表明MAPK途径中趋同的基因组进化可能是对FGFRi获得性耐药的潜在机制。
NCT02052778。
我们评估了先前接受成纤维细胞生长因子受体（FGFR）抑制剂治疗患者的肿瘤和血浆，FGFR是一种重要的受体，在癌细胞生长中起作用，尤其是在该基因存在异常的肿瘤中，如FGFR融合，即FGFR基因与另一个基因融合，导致癌细胞生长激活。我们发现接受FGFR抑制剂治疗的患者可能在其他基因如KRAS中发生突变，这可导致对FGFR抑制剂耐药。这些发现对FGFR2融合阳性肿瘤患者有多重意义，并为新出现的MAPK途径改变提供了机制性见解，这些改变可能是FGFRi获得性耐药情况下的治疗靶点。
