提高SLFN11的表达

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SLFN11表达高活性强，top1抑制剂（伊立替康、拓扑替康、后端是top1抑制剂的ADC药物如8201、SG）、top2抑制剂（依托泊苷、柔红霉素、米托蒽醌）、top1/top2抑制剂（多柔比星、表柔比星）、铂类化疗药、DNA 合成抑制剂（吉西他滨、氟达拉滨、阿糖胞苷、羟基脲和核苷类似物）、parp抑制剂（奥拉帕尼、尼拉帕尼、他拉唑帕尼）等DNA损伤剂疗效好。

可以用药提高SLFN11的表达：

一、表观遗传作用机制药物

1、DNMT抑制剂

《Epigenetically upregulating TROP2 and SLFN11 enhances therapeutic efficacy of TROP2 antibody drug conjugate sacitizumab govitecan》

TROP2 antibody drug conjugates (ADCs) are under active development. We seek to determine whether we can enhance activity of TROP2 ADCs by increasing TROP2 expression. In metaplastic breast cancers (MpBC), there is limited expression of TROP2, and downregulating transcription factor ZEB1 upregulates E-cad and TROP2, thus sensitizing cancers to TROP2 ADC sacituzumab govitecan (SG). Demethylating agent decitabine decreases DNA methyltransferase expression and TROP2 promoter methylation and subsequently increases TROP2 expression. Decitabine treatment as well as overexpression of TROP2 significantly enhance SG antitumor activity. Decitabine also increases SLFN11, a biomarker of topoisomerase 1 inhibitor (TOP1) sensitivity and is synergistic with SG which has a TOP1 payload, in TROP2-expressing SLFN11-low BC cells. In conclusion, TROP2 and SLFN11 expression can be epigenetically modulated and the combination of demethylating agent decitabine with TROP2 ADCs may represent a novel therapeutic approach for tumors with low TROP2 or SLFN11 expression.

DNMT抑制剂有地西他滨等药。

地西他滨既升高DNMT，又升高TROP2，是前端是trop2抑制剂后端是top1抑制剂的SG等ADC药物的双效增敏增效剂。

2、 I 类HDAC抑制剂而非 II 类HDAC抑制剂

《Overcoming Resistance to DNA-Targeted Agents by Epigenetic Activation of Schlafen 11 (SLFN11) Expression with Class I Histone Deacetylase Inhibitors》

SLFN11 expression is suppressed in a broad fraction of common cancers and cancer cell lines. In cancer cells not expressing SLFN11, transfection of SLFN11 sensitized the cells to camptothecin, topotecan, hydroxyurea, and cisplatin but not to paclitaxel. SLFN11 mRNA and protein levels were strongly induced by class I (romidepsin, entinostat), but not class II (roclinostat) HDAC inhibitors in a broad panel of cancer cells. SLFN11 expression was also enhanced in peripheral blood mononuclear cells of patients with circulating cutaneous T-cell lymphoma treated with romidepsin. Consistent with the epigenetic regulation of SLFN11, camptothecin and class I HDAC inhibitors were synergistic in many of the cell lines tested.

I 类HDAC抑制剂有西达本胺等药物。

3、EZH2抑制剂

1、《Abstract 3264: Ex vivo treatment in high grade serous ovarian cancer demonstrates the benefit of EZH2 inhibition in combination with standard therapy》

. Further assessment of DF216 via western blot analysis showed elevated expression of SLFN11 after 7 days of EZH2i treatment.

2、《Chemosensitive Relapse in Small Cell Lung Cancer Proceeds through an EZH2-SLFN11 Axis》

In vivo silencing of SLFN11 was associated with marked deposition of H3K27me3, a histone modification placed by EZH2, within the gene body of SLFN11, inducing local chromatin condensation and gene silencing. Inclusion of an EZH2 inhibitor with standard cytotoxic therapies prevented emergence of acquired resistance and augmented chemotherapeutic efficacy in both chemosensitive and chemoresistant models of small cell lung cancer.

二、多西环素

1、《SLFN11 Inactivation Induces Proteotoxic Stress and Sensitizes Cancer Cells to Ubiquitin Activating Enzyme Inhibitor TAK-243》

To confirm that the presence of SLFN11 influences the global ubiquitination at the steady-state condition, we generated doxycycline-inducible SLFN11-expressing cells. Seventy-two-hour exposure to doxycycline-induced robust SLFN11 expression

2、《SLFN11 inhibits checkpoint maintenance and homologous recombination repair》

As shown in Fig 4B, the expression of wild‐type SLFN11 was induced in HeLa cells when the cells were treated with doxycycline.

3、《Epigenetic upregulation of Schlafen11 renders  WNT- and SHH-activated medulloblastomas sensitive to cisplatin》

In contrast, SLFN11 overexpression in D425 cells using doxycycline (DOX)-inducible constructs increased cytotoxicity of cisplatin and SN-38, the active metabolite of irinotecan, which was evidenced by increased C-PARP (Figure 3F) and decreased cell viability (Figure 3G, H).

4、《Eltrombopag inhibits the proliferation of Ewing sarcoma cells via iron chelation and impaired DNA replication》

Next, we used a doxycycline-inducible system to express SLFN11 in a fibrosarcoma cell line, HT1080, that does not normally express SLFN11 (Fig. (Fig.6f)6f)

多西环素还升高her2的表达，因此多西环素是her2低表达患者用前端是her2抑制剂后端是top1抑制剂的8201等ADC药物的双效增敏增效剂。

三、SLFN11表达低失活导致的耐药可通过联用ATR抑制剂来逆转

1、《Resistance to PARP inhibitors by SLFN11 inactivation can be overcome by ATR inhibition》

The resistance to PARPIs by SLFN11 inactivation was overcome by ATR inhibition, mechanistically because SLFN11-deficient cells solely rely on ATR activation for their survival under PARPI treatment.

2、《Resistance to Pyrrolobenzodiazepine Dimers Is Associated with SLFN11 Downregulation and Can Be Reversed through Inhibition of ATR》

Moreover, we demonstrated that combining an ataxia telangiectasia and Rad3-related protein (ATR) inhibitor, AZD6738, with SG3199 or PBD-based ADCs led to synergistic cytotoxicity in either resistant 361-PBDr cells or cells that SLFN11 was knocked down via siRNA.

3、《SLFN11 promotes CDT1 degradation by CUL4 in response to replicative DNA damage, while its absence leads to synthetic lethality with ATR/CHK1 inhibitors》

our study reveals new chemotherapeutic insights on how targeting the ATR pathway overcomes chemoresistance of SLFN11-deficient cancers.

ATR抑制剂有cerasertib(azd6738)药物。

[基础知识] 提高SLFN11的表达

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