State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China.
Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China.
Eur J Cancer. 2021 Mar;145:92-108. doi: 10.1016/j.ejca.2020.11.045. Epub 2021 Jan 9.
Alhtough anti-HER2 tyrosine kinase inhibitors (TKIs) have radically prolonged survival and improved prognosis in HER2-positive breast cancer patients, resistance to these therapies is a constant obstacle leading to TKIs treatment failure and tumour progression.
To develop new strategies to enhance TKIs efficiency by combining synergistic gene targets, we performed panel library screening using the CRISPR/Cas9 knockout technique based on data mining across TCGA data sets and verified the candidate target in preclinical models and breast cancer high-throughput sequencing data sets.
We identified that CDK12, co-amplified with HER2 in a high frequency, is powerful to sensitise or resensitise HER2-positive breast cancer to anti-HER2 TKIs lapatinib, evidenced by patient-derived organoids in vitro and cell-derived xenograft or patient-derived xenograft in vivo. Exploring mechanisms, we found that inhibition of CDK12 attenuated PI3K/AKT signal, which usually serves as an oncogenic driver and is reactivated when HER2-positive breast cancers develop resistance to lapatinib. Combining CDK12 inhibition exerted additional suppression on p-AKT activation induced by anti-HER2 TKIs lapatinib treatment. Clinically, via DNA sequencing data for tumour tissue and peripheral blood ctDNA, we found that HER2-positive breast cancer patients with CDK12 amplification responded more insensitively to anti-HER2 treatment than those without accompanying CDK12 amplification by harbouring a markedly shortened progression-free survival (PFS) (median PFS: 4.3 months versus 6.9 months; hazards ratio [HR] = 2.26 [95% confidence interval [CI] = 1.32-3.86]; P = 0.0028).
Dual inhibition of HER2/CDK12 will prominently benefit the outcomes of patients with HER2-positive breast cancer by sensitising or resensitising the tumours to anti-HER2 TKIs treatment.
虽然抗 HER2 酪氨酸激酶抑制剂（TKI）已极大地延长了 HER2 阳性乳腺癌患者的生存时间并改善了预后，但对这些治疗的耐药性是导致 TKI 治疗失败和肿瘤进展的持续障碍。
为了通过结合协同基因靶点来开发增强 TKI 效率的新策略，我们使用基于 TCGA 数据集数据挖掘的 CRISPR/Cas9 敲除技术进行了面板文库筛选，并在临床前模型和乳腺癌高通量测序数据集中验证了候选靶点。
我们发现 CDK12 与 HER2 高频共扩增，能够使 HER2 阳性乳腺癌对抗 HER2 TKI 拉帕替尼敏感或重新敏感，这一点在体外患者来源的类器官和细胞衍生的异种移植或患者来源的异种移植中得到了证实。通过机制探索，我们发现抑制 CDK12 可减弱 PI3K/AKT 信号，该信号通常作为致癌驱动因素，当 HER2 阳性乳腺癌对拉帕替尼产生耐药性时会被重新激活。联合 CDK12 抑制作用可进一步抑制抗 HER2 TKI 拉帕替尼治疗引起的 p-AKT 激活。临床上，通过肿瘤组织和外周血 ctDNA 的 DNA 测序数据，我们发现 HER2 阳性乳腺癌患者中 CDK12 扩增与对抗 HER2 治疗的敏感性降低相关，其无伴随 CDK12 扩增的患者具有更短的无进展生存期（中位 PFS：4.3 个月 vs. 6.9 个月；风险比[HR] = 2.26 [95%置信区间[CI] = 1.32-3.86]；P = 0.0028）。
双重抑制 HER2/CDK12 将通过使肿瘤对抗 HER2 TKI 治疗敏感或重新敏感，显著改善 HER2 阳性乳腺癌患者的结局。
