RB expression confers sensitivity to CDK4/6 inhibitor-mediated radiosensitization across breast cancer subtypes.
RB expression confers sensitivity to CDK4/6 inhibitor-mediated radiosensitization across breast cancer subtypes.
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DOI：
10.1172/jci.insight.154402
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发表时间：
2022-02-08
期刊：
影响因子：
8
通讯作者：
Speers CW
中科院分区：
文献类型：
--
作者：
Pesch AM;Hirsh NH;Michmerhuizen AR;Jungles KM;Wilder-Romans K;Chandler BC;Liu M;Lerner LM;Nino CA;Ward C;Cobain EF;Lawrence TS;Pierce LJ;Rae JM;Speers CW
标准放射治疗（RT）不能可靠地为患有多结节阳性乳腺癌和三阴性乳腺癌（TNBC）的女性提供局部控制。我们假设CDK 4/6抑制（CDK 4/6 i）不仅会增加雌激素受体阳性（ER+）细胞的放射敏感性，而且还会增加表达视网膜母细胞瘤（RB）蛋白的TNBC的放射敏感性。我们发现，CDK 4/6 i放射增敏RB WT TNBC（n = 4，放射增强比[rER]：1.49-2.22），但未能放射增敏RB-无效TNBC（n = 3，rER：0.84-1.00）。RB表达预测对CDK 4/6 i + RT的反应（R2 = 0.84），并且在同基因和非同基因模型中RB 1敲低后，ER+/TNBC细胞中的放射增敏作用丧失（rER：0.88-1.13）。CDK 4/6 i抑制RB WT细胞中的同源重组（HR），但不抑制RB缺失细胞或RB 1缺失的同基因模型中的同源重组（HR）; RB再表达挽救了HR能力。放射增敏独立于非同源末端连接和CDK 4/6 i对细胞周期阻滞的已知作用。在机制上，RB和RAD 51在体外相互作用以促进HR修复。CDK 4/6 i在TNBC异种移植物中产生RB依赖性放射增敏作用，但在同基因RB 1缺失异种移植物中不产生。我们的数据为临床试验提供了临床前依据，该临床试验将CDK 4/6 i + RT的使用扩展到难以控制的RB完整乳腺癌（包括TNBC），并将RB状态指定为治疗效果的预测生物标志物。
Standard radiation therapy (RT) does not reliably provide locoregional control for women with multinode-positive breast cancer and triple-negative breast cancer (TNBC). We hypothesized that CDK4/6 inhibition (CDK4/6i) would increase the radiosensitivity not only of estrogen receptor–positive (ER+) cells, but also of TNBC that expresses retinoblastoma (RB) protein. We found that CDK4/6i radiosensitized RB WT TNBC (n = 4, radiation enhancement ratio [rER]: 1.49–2.22) but failed to radiosensitize RB-null TNBC (n = 3, rER: 0.84–1.00). RB expression predicted response to CDK4/6i + RT (R2 = 0.84), and radiosensitization was lost in ER+/TNBC cells (rER: 0.88–1.13) after RB1 knockdown in isogenic and nonisogenic models. CDK4/6i suppressed homologous recombination (HR) in RB WT cells but not in RB-null cells or isogenic models of RB1 loss; HR competency was rescued with RB reexpression. Radiosensitization was independent of nonhomologous end joining and the known effects of CDK4/6i on cell cycle arrest. Mechanistically, RB and RAD51 interact in vitro to promote HR repair. CDK4/6i produced RB-dependent radiosensitization in TNBC xenografts but not in isogenic RB1-null xenografts. Our data provide the preclinical rationale for a clinical trial expanding the use of CDK4/6i + RT to difficult-to-control RB-intact breast cancers (including TNBC) and nominate RB status as a predictive biomarker of therapeutic efficacy.
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影响因子：
5
作者：
David S;Ho G;Day D;Harris M;Tan J;Goel S;Hanna GG;Srivastava R;Kruss G;McDowell L;White M
通讯作者：
White M
DOI：
10.1200/jco.20.02514
发表时间：
2020-12-01
期刊：
Journal of clinical oncology : official journal of the American Society of Clinical Oncology
影响因子：
--
作者：
Johnston SRD;Harbeck N;Hegg R;Toi M;Martin M;Shao ZM;Zhang QY;Martinez Rodriguez JL;Campone M;Hamilton E;Sohn J;Guarneri V;Okada M;Boyle F;Neven P;Cortés J;Huober J;Wardley A;Tolaney SM;Cicin I;Smith IC;Frenzel M;Headley D;Wei R;San Antonio B;Hulstijn M;Cox J;O'Shaughnessy J;Rastogi P;monarchE Committee Members and Investigators
通讯作者：
monarchE Committee Members and Investigators
影响因子：
5.6
作者：
Jiang Y;Yam JC;Tham CC;Pang CP;Chu WK
通讯作者：
Chu WK
影响因子：
11.5
作者：
Kettner, Nicole M.;Vijayaraghavan, Smruthi;Keyomarsi, Khandan
通讯作者：
Keyomarsi, Khandan
影响因子：
51.1
作者：
Finn, Richard S.;Crown, John P.;Slamon, Dennis J.
通讯作者：
Slamon, Dennis J.