Finding indicators to predict how breast cancer will respond to decitabine treatment based on the drug's mode-of-action

The Canadian Cancer Society estimates that 13 Canadian women will die from breast cancer every day. Epigenetic modifications, like aberrant DNA methylation contribute to breast cancer progression and must be addressed to improve patient outcomes. DNA hypermethylation can inhibit the expression of tumor suppressor genes (TSGs), which contributes to the development and progression of cancer. Using a de-methylating agent such as decitabine (5-aza-2'-deoxycytidine), results in the re-expression or induction of TSGs. Although this effect has been well documented in cancer, it may not be the main contributor to decitabine sensitivity. Other aspects of decitabine treatment, such as the induction of an interferon response have also been suggested as contributors to decitabine sensitivity. Using a representative panel of breast cancer cell lines with varying sensitivities to decitabine, these possible effects of decitabine will be evaluated to reveal their value in predicting decitabine response. Using quantitative polymerase chain reaction (qPCR), expression of genes associated with TSG induction and the interferon response were analyzed to reveal the predominate class of genes that are induced upon treatment. It was found that neither class of gene was indicative of decitabine sensitivity. Alternative factors that might predict decitabine sensitivity were evaluated; these factors all have well-established roles in decitabine’s mode-of-action. Decitabine must be imported, processed and incorporated into the DNA. It was found that incorporation into the DNA is also not predictive of decitabine sensitivity. Next, genes associated with import/export, processing and de-methylating effects of decitabine were evaluated for any association with decitabine sensitivity. Relatively strong correlations with the import gene SLC28A1, the processing gene DCK as well as the DNMT1A and DNMT3B de methylating genes were found. This suggests that these four genes may be important mediators of decitabine sensitivity in breast cancer, and could be useful in predicting patient response to this new therapy

Dying to Be Noticed: Epigenetic Regulation of Immunogenic Cell Death for Cancer Immunotherapy

International audienceImmunogenic cell death (ICD) activates both innate and adaptive arms of the immune system during apoptotic cancer cell death. With respect to cancer immunotherapy, the process of ICD elicits enhanced adjuvanticity and antigenicity from dying cancer cells and consequently, promotes the development of clinically desired antitumor immunity. Cancer ICD requires the presentation of various " hallmarks " of immunomodulation, which include the cell-surface translocation of calreticulin, production of type I interferons, and release of high-mobility group box-1 and ATP, which through their compatible actions induce an immune response against cancer cells. Interestingly, recent reports investigating the use of epigenetic modifying drugs as anticancer therapeutics have identified several connections to ICD hallmarks. Epigenetic modifiers have a direct effect on cell viability and appear to fundamentally change the immunogenic properties of cancer cells, by actively subverting tumor microenvironment-associated immunoevasion and aiding in the development of an antitumor immune response. In this review, we critically discuss the current evidence that identifies direct links between epigenetic modifications and ICD hallmarks, and put forward an otherwise poorly understood role for epigenetic drugs as ICD inducers. We further discuss potential therapeutic innovations that aim to induce ICD during epigenetic drug therapy, generating highly efficacious cancer immunotherapies

Dying to Be Noticed: Epigenetic Regulation of Immunogenic Cell Death for Cancer Immunotherapy

Immunogenic cell death (ICD) activates both innate and adaptive arms of the immune system during apoptotic cancer cell death. With respect to cancer immunotherapy, the process of ICD elicits enhanced adjuvanticity and antigenicity from dying cancer cells and consequently, promotes the development of clinically desired antitumor immunity. Cancer ICD requires the presentation of various “hallmarks” of immunomodulation, which include the cell-surface translocation of calreticulin, production of type I interferons, and release of high-mobility group box-1 and ATP, which through their compatible actions induce an immune response against cancer cells. Interestingly, recent reports investigating the use of epigenetic modifying drugs as anticancer therapeutics have identified several connections to ICD hallmarks. Epigenetic modifiers have a direct effect on cell viability and appear to fundamentally change the immunogenic properties of cancer cells, by actively subverting tumor microenvironment-associated immunoevasion and aiding in the development of an antitumor immune response. In this review, we critically discuss the current evidence that identifies direct links between epigenetic modifications and ICD hallmarks, and put forward an otherwise poorly understood role for epigenetic drugs as ICD inducers. We further discuss potential therapeutic innovations that aim to induce ICD during epigenetic drug therapy, generating highly efficacious cancer immunotherapies

Decitabine Response in Breast Cancer Requires Efficient Drug Processing and Is Not Limited by Multidrug Resistance

Dysregulation of DNA methylation is an established feature of breast cancers. DNA demethylating therapies like decitabine are proposed for the treatment of triple-negative breast cancers (TNBC) and indicators of response need to be identified. For this purpose, we characterized the effects of decitabine in a panel of 10 breast cancer cell lines and observed a range of sensitivity to decitabine that was not subtype specific. Knockdown of potential key effectors demonstrated the requirement of deoxycytidine kinase (DCK) for decitabine response in breast cancer cells. In treatment-naïve breast tumors, DCK was higher in TNBCs, and DCK levels were sustained or increased post chemotherapy treatment. This suggests that limited DCK levels will not be a barrier to response in patients with TNBC treated with decitabine as a second-line treatment or in a clinical trial. Methylome analysis revealed that genome-wide, region-specific, tumor suppressor gene–specific methylation, and decitabine-induced demethylation did not predict response to decitabine. Gene set enrichment analysis of transcriptome data demonstrated that decitabine induced genes within apoptosis, cell cycle, stress, and immune pathways. Induced genes included those characterized by the viral mimicry response; however, knockdown of key effectors of the pathway did not affect decitabine sensitivity suggesting that breast cancer growth suppression by decitabine is independent of viral mimicry. Finally, taxol-resistant breast cancer cells expressing high levels of multidrug resistance transporter ABCB1 remained sensitive to decitabine, suggesting that the drug could be used as second-line treatment for chemoresistant patients