CDK4/6 inhibitors target SMARCA4-determined cyclin D1 deficiency in hypercalcemic small cell carcinoma of the ovary (II)

Inactivating mutations in SMARCA4 (BRG1), a key SWI/SNF chromatin remodelling gene, underlie small cell carcinoma of the ovary, hypercalcemic type (SCCOHT). To reveal its druggable vulnerabilities, we perform kinase-focused RNAi screens and uncover that SMARCA4-deficient SCCOHT cells are highly sensitive to the inhibition of cyclin-dependent kinase 4/6 (CDK4/6). SMARCA4 loss causes profound downregulation of cyclin D1, which limits CDK4/6 kinase activity in SCCOHT cells and leads to in vitro and in vivo susceptibility to CDK4/6 inhibitors. SCCOHT patient tumors are deficient in cyclin D1 yet retain the retinoblastoma-proficient/p16INK4a-deficient profile associated with positive responses to CDK4/6 inhibitors. Thus, our findings indicate that CDK4/6 inhibitors, approved for a breast cancer subtype addicted to CDK4/6 activation, could be repurposed to treat SCCOHT. Moreover, our study suggests a novel paradigm whereby critically low oncogene levels, caused by loss of a driver tumor suppressor, may also be exploited therapeutically. The effect of CDK6 knockdown and palbociclib treatment on SCCOHT cells.

作为SWI/SNF染色质重塑关键基因的SMARCA4（BRG1）发生失活突变，是高钙血症型卵巢小细胞癌（SCCOHT）的致病根源。为揭示该疾病的可靶向治疗脆弱靶点，我们开展了激酶靶向RNA干扰筛选，发现SMARCA4缺陷型SCCOHT细胞对细胞周期蛋白依赖性激酶4/6（CDK4/6）的抑制作用呈现高度敏感性。SMARCA4缺失会显著下调细胞周期蛋白D1的表达，这会限制SCCOHT细胞内的CDK4/6激酶活性，进而使细胞在体外及体内均对CDK4/6抑制剂产生易感性。SCCOHT患者的肿瘤组织存在细胞周期蛋白D1缺陷，但却保留了与CDK4/6抑制剂阳性应答相关的视网膜母细胞瘤蛋白阳性/p16INK4a阴性表型。据此，我们的研究结果表明，原本获批用于治疗一类依赖CDK4/6激活的乳腺癌亚型的CDK4/6抑制剂，可被重新定位用于SCCOHT的临床治疗。此外，本研究提出了一种全新的治疗范式：由驱动性肿瘤抑制因子缺失所导致的极低水平致癌基因表达，同样可被用于靶向治疗。本研究同时验证了CDK6敲降及帕博西尼治疗对SCCOHT细胞的作用效果。