A Deregulated HOX Gene Axis Confers an Epigenetic Vulnerability in KRAS-Mutant Lung Cancers.,Cancer Cell

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A Deregulated HOX Gene Axis Confers an Epigenetic Vulnerability in KRAS-Mutant Lung Cancers.
Cancer Cell ( IF 50.3 ) Pub Date : 2020-04-02 , DOI: 10.1016/j.ccell.2020.03.004
Stephanie L Guerra ₁ , Ophélia Maertens ₁ , Ryan Kuzmickas ₁ , Thomas De Raedt ₁ , Richard O Adeyemi ₁ , Caroline J Guild ₁ , Shawna Guillemette ₁ , Amanda J Redig ₂ , Emily S Chambers ₂ , Man Xu ₃ , Hong Tiv ₄ , Sandro Santagata ₅ , Pasi A Jänne ₆ , Stephen J Elledge ₇ , Karen Cichowski ₈

Affiliation

Genetics Division, Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA; Harvard Medical School, Boston, MA 02115, USA.
Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
Belfer Center for Applied Cancer Science, Boston, MA 02115, USA.
Experimental Therapeutic Core, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
Harvard Medical School, Boston, MA 02115, USA; Departments of Pathology, Brigham and Women's Hospital, Dana-Farber Cancer Institute, Boston, MA 02115, USA; Ludwig Center at Harvard, Harvard Medical School, Boston, MA 02115, USA.
Harvard Medical School, Boston, MA 02115, USA; Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA; Belfer Center for Applied Cancer Science, Boston, MA 02115, USA.
Genetics Division, Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA; Ludwig Center at Harvard, Harvard Medical School, Boston, MA 02115, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA; Howard Hughes Medical Institute, 77 Avenue Louis Pasteur, Boston, MA 02115, USA.
Genetics Division, Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA; Harvard Medical School, Boston, MA 02115, USA; Ludwig Center at Harvard, Harvard Medical School, Boston, MA 02115, USA.

While KRAS mutations are common in non-small cell lung cancer (NSCLC), effective treatments are lacking. Here, we report that half of KRAS-mutant NSCLCs aberrantly express the homeobox protein HOXC10, largely due to unappreciated defects in PRC2, which confers sensitivity to combined BET/MEK inhibitors in xenograft and PDX models. Efficacy of the combination is dependent on suppression of HOXC10 by BET inhibitors. We further show that HOXC10 regulates the expression of pre-replication complex (pre-RC) proteins in sensitive tumors. Accordingly, BET/MEK inhibitors suppress pre-RC proteins in cycling cells, triggering stalled replication, DNA damage, and death. These studies reveal a promising therapeutic strategy for KRAS-mutant NSCLCs, identify a predictive biomarker of response, and define a subset of NSCLCs with a targetable epigenetic vulnerability.

中文翻译：

失调的 HOX 基因轴赋予 KRAS 突变肺癌表观遗传脆弱性。

虽然 KRAS 突变在非小细胞肺癌 (NSCLC) 中很常见，但缺乏有效的治疗方法。在这里，我们报告说，一半的 KRAS 突变 NSCLC 异常表达同源框蛋白 HOXC10，这主要是由于 PRC2 中未被识别的缺陷，这赋予异种移植和 PDX 模型中组合 BET/MEK 抑制剂的敏感性。组合的功效取决于 BET 抑制剂对 HOXC10 的抑制。我们进一步表明 HOXC10 调节敏感肿瘤中复制前复合体 (pre-RC) 蛋白的表达。因此，BET/MEK 抑制剂抑制循环细胞中的前 RC 蛋白，引发停滞的复制、DNA 损伤和死亡。这些研究揭示了 KRAS 突变 NSCLC 的一种有前途的治疗策略，确定了反应的预测性生物标志物，

更新日期：2020-04-02

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