Understanding and Overcoming Resistance to Selective FGFR Inhibitors across FGFR2-Driven Malignancies.

IF 10 1区 医学 Q1 ONCOLOGY
Francesco Facchinetti, Yohann Loriot, Floriane Brayé, Damien Vasseur, Rastislav Bahleda, Ludovic Bigot, Rémy Barbé, Catline Nobre, David Combarel, Stefan Michiels, Antoine Italiano, Cristina Smolenschi, Lambros Tselikas, Jean-Yves Scoazec, Santiago Ponce-Aix, Benjamin Besse, Fabrice André, Ken A Olaussen, Antoine Hollebecque, Luc Friboulet
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引用次数: 0

Abstract

Purpose: Understanding resistance to selective FGFR inhibitors is crucial to improve the clinical outcomes of patients with FGFR2-driven malignancies.

Experimental design: We analyzed sequential ctDNA, ± whole-exome sequencing, or targeted next-generation sequencing on tissue biopsies from patients with tumors harboring activating FGFR2 alterations progressing on pan-FGFR-selective inhibitors, collected in the prospective UNLOCK program. FGFR2::BICC1 Ba/F3 and patient-derived xenograft models were used for functional studies.

Results: Thirty-six patients were included. In cholangiocarcinoma, at resistance to both reversible inhibitors (e.g., pemigatinib and erdafitinib) and the irreversible inhibitor futibatinib, polyclonal FGFR2 kinase domain mutations were frequent (14/27 patients). Tumors other than cholangiocarcinoma shared the same mutated FGFR2 residues, but polyclonality was rare (1/9 patients). At resistance to reversible inhibitors, 14 residues in the FGFR2 kinase domain were mutated-after futibatinib, only the molecular brake N550 and the gatekeeper V565. Off-target alterations in PI3K/mTOR and MAPK pathways were found in 11 patients, often together with on-target mutations. At progression to a first FGFR inhibitor, 12 patients received futibatinib or lirafugratinib (irreversible inhibitors), with variable clinical outcomes depending on previous resistance mechanisms. Two patients with TSC1 or PIK3CA mutations benefited from everolimus. In cell viability assays on Ba/F3 and in pharmacologic studies on patient-derived xenografts, irreversible inhibitors retained better activity against FGFR2 kinase domain mutations, with lirafugratinib active against the recalcitrant V565L/F/Y.

Conclusions: At progression to FGFR inhibitors, FGFR2-driven malignancies are characterized by high intra- and interpatient molecular heterogeneity, particularly in cholangiocarcinoma. Resistance to FGFR inhibitors can be overcome by sequential, molecularly oriented treatment strategies across FGFR2-driven tumors.

了解和克服 FGFR2 驱动的恶性肿瘤对选择性 FGFR 抑制剂的耐药性。
目的:了解选择性 FGFR 抑制剂的耐药性对于改善 FGFR2 驱动的恶性肿瘤患者的临床预后至关重要:我们分析了前瞻性 UNLOCK 计划中收集的、携带活化 FGFR2 改变的肿瘤患者组织活检的连续 ctDNA、+/- WES 或靶向 NGS。FGFR2::BICC1 Ba/F3和患者衍生异种移植(PDX)模型被用于功能研究:结果:共纳入 36 例患者。在胆管癌中,对可逆抑制剂(如培米加替尼、厄达非替尼)和不可逆抑制剂福替替尼耐药时,多克隆FGFR2激酶域突变很常见(14/27例患者)。胆管癌以外的其他肿瘤也存在相同的FGFR2残基突变,但多克隆现象很少见(1/9例患者)。在对可逆抑制剂产生耐药性时,FGFR2激酶结构域中有14个残基发生突变;在使用氟替尼后,只有分子制动器N550和守门员V565发生突变。在11例患者中发现了PI3K/mTOR和MAPK通路的非靶向改变,通常与靶向突变同时发生。在首次使用表皮生长因子受体(FGFR)抑制剂时,12名患者接受了氟替替尼或利拉呋替尼(不可逆抑制剂)治疗,临床结果因先前的耐药机制而异。两名 TSC1 或 PIK3CA 基因突变的患者从依维莫司中获益。在Ba/F3细胞活力测定和PDX药理学研究中,不可逆抑制剂对FGFR2激酶域突变具有更好的活性,其中利拉伐替尼对难治性V565L/F/Y具有活性:结论:在对FGFR抑制剂产生耐药性时,FGFR2驱动的恶性肿瘤具有高度的患者内和患者间分子异质性,特别是在胆管癌中。在FGFR2驱动的肿瘤中,可以通过以分子为导向的连续治疗策略克服对FGFR抑制剂的耐药性。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Clinical Cancer Research
Clinical Cancer Research 医学-肿瘤学
CiteScore
20.10
自引率
1.70%
发文量
1207
审稿时长
2.1 months
期刊介绍: Clinical Cancer Research is a journal focusing on groundbreaking research in cancer, specifically in the areas where the laboratory and the clinic intersect. Our primary interest lies in clinical trials that investigate novel treatments, accompanied by research on pharmacology, molecular alterations, and biomarkers that can predict response or resistance to these treatments. Furthermore, we prioritize laboratory and animal studies that explore new drugs and targeted agents with the potential to advance to clinical trials. We also encourage research on targetable mechanisms of cancer development, progression, and metastasis.
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