Aberrant FGFR signaling mediates resistance to CDK4/6 inhibitors in ER plus breast cancer
Aberrant FGFR signaling mediates resistance to CDK4/6 inhibitors in ER plus breast cancer
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DOI：
10.1038/s41467-019-09068-2
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发表时间：
2019-03-26
影响因子：
16.6
通讯作者：
Arteaga, Carlos L.
中科院分区：
文献类型：
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作者：
Formisano, Luigi;Lu, Yao;Arteaga, Carlos L.
在用CDK 4/6抑制剂ribociclib加氟维司群处理的MCF-7细胞中使用ORF激酶组筛选，我们将FGFR 1鉴定为耐药机制。FGFR 1扩增/ER+乳腺癌细胞和FGFR 1转导的MCF-7细胞对氟维司群+/- ribociclib或palbociclib耐药。通过用FGFR酪氨酸激酶抑制剂（TKI）lucitanib治疗消除这种抗性。在palbociclib/氟维司群中添加FGFR TKI erdafitinib可诱导FGFR 1扩增/ER+患者源性异种移植物的完全缓解。在CDK 4/6抑制剂治疗进展后，对34例患者的循环肿瘤DNA（ctDNA）进行了下一代测序，在14/34（41%）例进展后标本中发现了FGFR 1/2扩增或激活突变。最后，来自入选ribociclib注册试验MONALEESA-2的患者的ctDNA显示，与野生型FGFR 1患者相比，FGFR 1扩增患者的无进展生存期较短。因此，我们建议在使用ER、CDK 4/6和FGFR拮抗剂组合的试验中应考虑FGFR通路改变的乳腺癌。
Using an ORF kinome screen in MCF-7 cells treated with the CDK4/6 inhibitor ribociclib plus fulvestrant, we identified FGFR1 as a mechanism of drug resistance. FGFR1-amplified/ER+ breast cancer cells and MCF-7 cells transduced with FGFR1 were resistant to fulvestrant +/- ribociclib or palbociclib. This resistance was abrogated by treatment with the FGFR tyrosine kinase inhibitor (TKI) lucitanib. Addition of the FGFR TKI erdafitinib to palbociclib/fulvestrant induced complete responses of FGFR1-amplified/ER+ patient-derived-xenografts. Next generation sequencing of circulating tumor DNA (ctDNA) in 34 patients after progression on CDK4/6 inhibitors identified FGFR1/2 amplification or activating mutations in 14/34 (41%) post-progression specimens. Finally, ctDNA from patients enrolled in MONALEESA-2, the registration trial of ribociclib, showed that patients with FGFR1 amplification exhibited a shorter progression-free survival compared to patients with wild type FGFR1. Thus, we propose breast cancers with FGFR pathway alterations should be considered for trials using combinations of ER, CDK4/6 and FGFR antagonists.