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Table 1 Studies of treatment-induced resistant phenotypes and common characteristics

From: Emerging roles of H3K9me3, SETDB1 and SETDB2 in therapy-induced cellular reprogramming

Model(s) used Treatment method(s) Treatment duration Characteristics observed in surviving cells Reference
Non-small-cell lung cancer (PC9, HCC827), melanoma (M14), colorectal cancer (Colo-205), breast cancer (MDA-MB175v2, SKBR3, HCC1419), gastric cancer (KATO II) Erlotinib (2 μM), AZ628 (2 μM), Lapatinib (2 μM), PF-2341066 (1 μM) 9 days, long-term assays up to > 30 days Phenotypic switching, drug insensitivity, mitogenic rewiring, global histone alterations [8]
Melanoma (11 BRAF mutant, 3 BRAF wild type), in vitro and in nude mice Vemurafenib (0 .5μM) 7 days G1 arrest, increased senescence markers, phenotypic switching, heterochromatin formation [40]
Melanoma (3 BRAF mutant, 1 NRAS mutant) Vemurafenib (250/500 nM), cisplatin (30 μM), low glucose media, hypoxia > 12 days, long-term assays up to 75 days Phenotypic switching, multi-drug insensitivity, dedifferentiation, increased angiogenic and tumorigenic potential, global histone alterations [5]
90 biopsies from melanoma patients pre- and on-treatment with disease progression MAPK-Targeted therapy (i.e. BRAF inhibitors, BRAF + MEK inhibitors) Highly recurrent transcriptomic alteration, mitogenic rewiring, increased resistance to both targeted therapy and immune checkpoint inhibitors [20]
Breast cancer (TSA) and melanoma (B16-F10) cells in vitro or implanted in mice Immune checkpoint inhibitors (anti-PD1, anti-CTLA4), type 1 and 2 IFNs < 16 days Increased IFN signalling, cross-resistance to anti-CTLA4 therapy via T cell receptor depletion, epigenomic alterations [6]
Leukaemia (L1210) Chemotherapeutics (Carmustine 2 .5 μg/mL, Vincristine 10 ng/mL, cytarabine 1 μg/mL) 18–24 h Increased drug resistance, survival significantly associated with reduced proliferation [16]
Non-small-cell lung cancer (PC9) and single-cell-derived subpopulations (PC9–1) Erlotinib (2 .5 μM), WZ8040 (0 .1 μM), WZ3146 (0 .1 μM), SGX-523 (0 .1 μM),
Crizotinib (31.6 nM), trichostatin A (20 nM)
14 days, long-term assays up to > 46 weeks Increased drug resistance, growth arrest, diverse mechanisms of gaining de novo resistance [2]
Non-small-cell lung cancer (PC9), colorectal cancer (SW480, Colo205), breast cancer (SKBR3, EVSAT), melanoma (M14, Hs888, C32), gastric cancer (GTL-16) Erlotinib (1 μM), GDC-0980 (2 μM), AZ628 (2 μM), Lapatinib (1 μM),
Vemurafenib (2 μM), 5-FU (33 μM), SN-38 (6 nM), crizotinib (1 μM)
7–28 days depending on cell line and treatment Increased drug resistance, growth arrest, global histone alterations, retroviral activation and subsequent repression by H3K9me3 [14]
Melanoma (WM989, WM983B, 1205Lu, SK-MEL-28), primary melanocytes Lapatinib (1 μM),
Vemurafenib (1 μM),
2–28 days Dedifferentiation, epigenetic reprogramming, rare co-expression of resistance genes, [12]
46 patient-matched melanomas pre- and on-treatment, 7 melanoma cell lines + murine melanoma in nude mice MAPK-targeted therapy (i.e. BRAF inhibitors, BRAF + MEK inhibitors) Highly recurrent transcriptomic alteration, increased mesenchymal and angiogenic potential, increased IFN signalling, decreased immune sensitivity [13]
Melanoma (WM164, WM1366), lung cancer (A549, HCC827), colon cancer (HT29), liver cancer (HEPG2), breast cancer (SKBR3) Dabrafenib (25 nM), Trametinib (10 nM), Erlotinib (5 μM), docetaxel (5 nM/30 nM), Doxorubicin (500 nM), cisplatin (80 nM), low glucose media 12–15 days Phenotypic switching, multi-drug insensitivity, global histone alterations, enriched IFN signalling [15]
Case study of metastatic melanoma patient, 8 melanoma cell lines Adoptive T cell therapy, TNFa supplementation Increased immunotherapy resistance, reversible and inflammation-induced dedifferentiation [7]
4 patient-derived primary B cell lymphomas, haematological malignancies (RCK8, EHEB, K562, Mec1), colorectal cancer (SW480, LS174T, DLD-1, Caco-2), melanoma (WM266.4, SK-Mel-28, MeWo, Omm 2.3) Adriamycin (0.01–0.05 μM), ICG-001 (1 μM), Salinomycin (1 μM), PD325901 (10 nM), PD98059 (25 μM), LY294002 (10 μM), MK-2206 (200 nM), CHIR99021 (1 μM) 2–7 days Dedifferentiation, phenotypic switching, increased drug resistance, increased tumorigenic potential, temporary senescence features, heterochromatin formation [28]