Decitabine potentiates efficacy of doxorubicin in a preclinical trastuzumab-resistant HER2-positive breast cancer models

Acquired drug resistance and metastasis in breast cancer (BC) are coupled with epigenetic deregulation of gene expression. Epigenetic drugs, aiming to reverse these aberrant transcriptional patterns and sensitize cancer cells to other therapies, provide a new treatment strategy for drug-resistant tumors. Here we investigated the ability of DNA methyltransferase (DNMT) inhibitor decitabine (DAC) to increase the sensitivity of BC cells to anthracycline antibiotic doxorubicin (DOX). Three cell lines representing different molecular BC subtypes, JIMT-1, MDA-MB-231 and T-47D, were used to evaluate the synergy of sequential DAC + DOX treatment in vitro. The cytotoxicity, genotoxicity, apoptosis, and migration capacity were tested in 2D and 3D cultures. Moreover, genome-wide DNA methylation and transcriptomic analyses were employed to understand the differences underlying DAC responsiveness. The ability of DAC to sensitize trastuzumab-resistant HER2-positive JIMT-1 cells to DOX was examined in vivo in an orthotopic xenograft mouse model. DAC and DOX synergistic effect was identified in all tested cell lines, with JIMT-1 cells being most sensitive to DAC. Based on the whole-genome data, we assume that the aggressive behavior of JIMT-1 cells can be related to the enrichment of epithelial-to-mesenchymal transition and stemness-associated pathways in this cell line. The four-week DAC + DOX sequential administration significantly reduced the tumor growth, DNMT1 expression, and global DNA methylation in xenograft tissues. The efficacy of combination therapy was comparable to effect of pegylated liposomal DOX, used exclusively for the treatment of metastatic BC. This work demonstrates the potential of epigenetic drugs to modulate cancer cells' sensitivity to other forms of anticancer therapy.publishedVersio

Genetic Engineering of Natural Killer Cells for Enhanced Antitumor Function

Natural Killer (NK) cells are unique immune cells capable of efficient killing of infected and transformed cells. Indeed, NK cell-based therapies induced response against hematological malignancies in the absence of adverse toxicity in clinical trials. Nevertheless, adoptive NK cell therapies are reported to have exhibited poor outcome against many solid tumors. This can be mainly attributed to limited infiltration of NK cells into solid tumors, downregulation of target antigens on the tumor cells, or suppression by the chemokines and secreted factors present within the tumor microenvironment. Several methods for genetic engineering of NK cells were established and consistently improved over the last decade, leading to the generation of novel NK cell products with enhanced anti-tumor activity and improved tumor homing. New generations of engineered NK cells are developed to better target refractory tumors and/or to overcome inhibitory tumor microenvironment. This review summarizes recent improvements in approaches to NK cell genetic engineering and strategies implemented to enhance NK cell effector functions

Genetic Engineering of Natural Killer Cells for Enhanced Antitumor Function

Natural Killer (NK) cells are unique immune cells capable of efficient killing of infected and transformed cells. Indeed, NK cell-based therapies induced response against hematological malignancies in the absence of adverse toxicity in clinical trials. Nevertheless, adoptive NK cell therapies are reported to have exhibited poor outcome against many solid tumors. This can be mainly attributed to limited infiltration of NK cells into solid tumors, downregulation of target antigens on the tumor cells, or suppression by the chemokines and secreted factors present within the tumor microenvironment. Several methods for genetic engineering of NK cells were established and consistently improved over the last decade, leading to the generation of novel NK cell products with enhanced anti-tumor activity and improved tumor homing. New generations of engineered NK cells are developed to better target refractory tumors and/or to overcome inhibitory tumor microenvironment. This review summarizes recent improvements in approaches to NK cell genetic engineering and strategies implemented to enhance NK cell effector functions

Additional file 3 of Natural killer cells in clinical development as non-engineered, engineered, and combination therapies

Additional file 3: Table S3. List of clinical trials with non-engineered combination NK cell therapies. N = 62 clinical trials (Phase I, II, or I/II) evaluating the infusion of non-engineered allogeneic NK cells in combination with other agents were registered on ClinicalTrials.gov until 31–12–2021. Studies are sorted by types of combination therapy (NK cell priming agents, Adoptive cell therapy, Antibodies, Co-stimulation, Multiple combinations, Molecular inhibitors and NK cell engagers). Details of the combination approach and the clinical trial design and outcome (when available) are presented. Trial status is updated to August 2022

Additional file 4 of Natural killer cells in clinical development as non-engineered, engineered, and combination therapies

Additional file 4: Table S4. List of clinical trials with engineered combination NK cell therapies. N = 34 clinical trials (Phase I, II, or I/II) evaluating the infusion of engineered allogeneic NK cells in combination with other agents were registered on ClinicalTrials.gov until 31–12–2021. Studies are sorted by types of combination therapy (Antibodies, Multiple combinations). Details of the combination approach and the clinical trial design and outcome (when available) are presented. Trial status is updated to August 2022

Additional file 2 of Natural killer cells in clinical development as non-engineered, engineered, and combination therapies

Additional file 2: Table S2. List of clinical trials with engineered NK cell therapies. N = 53 clinical trials (Phase I, II, or I/II) evaluating the infusion of engineered NK cell therapies in hematological or solid tumor patients were registered on ClinicalTrials.gov until 31–12–2021. Studies are sorted by NK cell source (PB-NK, UCB-NK, iPSCs, NK-92, Unknown). The type of engineered NK products (scFv-CAR-NK, Receptor-CAR-NK, CD16-engineered, or CD16- and scFv-engineered CAR-NK), the engineering method, transgene structure, and the clinical trial design and outcome (when available) are presented. Trial status is updated to August 2022. PB: peripheral blood; UCB: umbilical cord blood; iPSCs: induced pluripotent stem cells; scFv: single-chain variable fragment

Additional file 1 of Natural killer cells in clinical development as non-engineered, engineered, and combination therapies

Additional file 1: Table S1. List of clinical trials with non-engineered NK cell therapies. N = 36 clinical trials (Phase I, II, or I/II) evaluating the infusion of non-engineered allogeneic NK cell therapies in hematological or solid tumor patients were registered on ClinicalTrials.gov between March 2017 and December 2021. Studies are sorted by NK cell source (PB-NK, UCB-CD34, UCB-NK, iPSCs). The most relevant product characteristics and the clinical trial design and outcome (when available) are presented. Trial status is updated to August 2022. PB: peripheral blood; UCB: umbilical cord blood; iPSCs: induced pluripotent stem cells

Decitabine potentiates efficacy of doxorubicin in a preclinical trastuzumab-resistant HER2-positive breast cancer models

Acquired drug resistance and metastasis in breast cancer (BC) are coupled with epigenetic deregulation of gene expression. Epigenetic drugs, aiming to reverse these aberrant transcriptional patterns and sensitize cancer cells to other therapies, provide a new treatment strategy for drug-resistant tumors. Here we investigated the ability of DNA methyltransferase (DNMT) inhibitor decitabine (DAC) to increase the sensitivity of BC cells to anthracycline antibiotic doxorubicin (DOX). Three cell lines representing different molecular BC subtypes, JIMT-1, MDA-MB-231 and T-47D, were used to evaluate the synergy of sequential DAC + DOX treatment in vitro. The cytotoxicity, genotoxicity, apoptosis, and migration capacity were tested in 2D and 3D cultures. Moreover, genome-wide DNA methylation and transcriptomic analyses were employed to understand the differences underlying DAC responsiveness. The ability of DAC to sensitize trastuzumab-resistant HER2-positive JIMT-1 cells to DOX was examined in vivo in an orthotopic xenograft mouse model. DAC and DOX synergistic effect was identified in all tested cell lines, with JIMT-1 cells being most sensitive to DAC. Based on the whole-genome data, we assume that the aggressive behavior of JIMT-1 cells can be related to the enrichment of epithelial-to-mesenchymal transition and stemness-associated pathways in this cell line. The four-week DAC + DOX sequential administration significantly reduced the tumor growth, DNMT1 expression, and global DNA methylation in xenograft tissues. The efficacy of combination therapy was comparable to effect of pegylated liposomal DOX, used exclusively for the treatment of metastatic BC. This work demonstrates the potential of epigenetic drugs to modulate cancer cells' sensitivity to other forms of anticancer therapy

Decitabine potentiates efficacy of doxorubicin in a preclinical trastuzumab-resistant HER2-positive breast cancer models

Acquired drug resistance and metastasis in breast cancer (BC) are coupled with epigenetic deregulation of gene expression. Epigenetic drugs, aiming to reverse these aberrant transcriptional patterns and sensitize cancer cells to other therapies, provide a new treatment strategy for drug-resistant tumors. Here we investigated the ability of DNA methyltransferase (DNMT) inhibitor decitabine (DAC) to increase the sensitivity of BC cells to anthracycline antibiotic doxorubicin (DOX). Three cell lines representing different molecular BC subtypes, JIMT-1, MDA-MB-231 and T-47D, were used to evaluate the synergy of sequential DAC + DOX treatment in vitro. The cytotoxicity, genotoxicity, apoptosis, and migration capacity were tested in 2D and 3D cultures. Moreover, genome-wide DNA methylation and transcriptomic analyses were employed to understand the differences underlying DAC responsiveness. The ability of DAC to sensitize trastuzumab-resistant HER2-positive JIMT-1 cells to DOX was examined in vivo in an orthotopic xenograft mouse model. DAC and DOX synergistic effect was identified in all tested cell lines, with JIMT-1 cells being most sensitive to DAC. Based on the whole-genome data, we assume that the aggressive behavior of JIMT-1 cells can be related to the enrichment of epithelial-to-mesenchymal transition and stemness-associated pathways in this cell line. The four-week DAC + DOX sequential administration significantly reduced the tumor growth, DNMT1 expression, and global DNA methylation in xenograft tissues. The efficacy of combination therapy was comparable to effect of pegylated liposomal DOX, used exclusively for the treatment of metastatic BC. This work demonstrates the potential of epigenetic drugs to modulate cancer cells' sensitivity to other forms of anticancer therapy