The emergence of drug resistance to targeted cancer therapies: Clinical evidence. (December 2019)

• Record Type: Journal Article
• Authors: Sarmento-Ribeiro, Ana Bela; Scorilas, Andreas; Gonçalves, Ana Cristina; Efferth, Thomas; Trougakos, Ioannis P.
• Is Part Of: Drug resistance updates. Volume 47(2019)
• Publication Date: 2019-12
• Subjects: α-KG α-ketoglutarate -- 2-HG 2-hydroxyglutarate -- ABL Abelson kinase -- ADCC antibody dependent cellular cytotoxicity -- ADCs antibody-drug conjugates -- ADP antibody-dependent phagocytosis -- AGP α 1-acid glycoprotein -- ALK anaplastic lymphoma kinase -- ALL B-cell acute lymphoblastic leukemia -- ALP autophagy-lysosome pathway -- AML acute myeloid leukemia -- AMPK 5' adenosine monophosphate-activated protein kinase -- APCs antigen presenting cells -- APL acute promyelocytic leukemia -- APLs synthetic alkylphospholipids -- Ara C cytarabine -- Atg autophagy related gene -- ATO arsenic trioxide -- BCC basal cell carcinoma -- BCRP, ABCG2 breast cancer related protein -- BiTE bispecific T cell engager -- BsAbs bivalent bispecific antibodies -- BTK Bruton's tyrosine kinase -- CAFs cancer-associated fibroblasts -- CAR chimeric antigen receptor -- CDA cytidine deaminase -- CDC complement dependent cytotoxicity -- CI cancer immunotherapy -- CLL chronic lymphocytic leukemia -- CML chronic myeloid leukemia -- CMML chronic myelomonocytic leukemia -- CP 20S proteasome core particle -- CRBN-CRL4 E3 ubiquitin ligase cereblon -- CRC colorectal cancer -- CTCL cutaneous T-cell lymphoma -- CTLA-4 cytotoxic T lymphocyte antigen 4 -- Dbs diabodies -- dCK deoxycytidine kinase -- DIABLO IAP-binding mitochondrial protein -- EGF epidermal growth factor -- EGFR epidermal growth factor receptor -- EMA European Medicines Agency -- ER endoplasmic reticulum -- ERKs extracellular signal-regulated kinases -- FASLG FAS ligand -- FDA US Food and Drug Administration -- FGF fibroblast growth factor -- FGFR fibroblast growth factor receptor -- FLT3 fms-related tyrosine kinase 3 -- FOXO3 forkhead box O3 -- GIST gastrointestinal stromal tumors -- GRB2 growth factor bound 2 -- GST glutathione S-transferase -- HAT histone acetyltransferases -- hCNTs concentrative nucleoside transporters -- HCT hematopoietic stem cell transplantation -- HDAC6 microtubule-associated histone deacetylase 6 -- HDACis histone deacetylase inhibitors -- HDACs histone deacetylases -- hENTs nucleoside transporters -- HER2 human epidermal growth factor receptor 2 -- HGF hepatocyte growth factor -- Hh Hedgehog -- HMAs hypomethylating agents -- hNTs human nucleoside transporters -- hOCT1 human organic cation transporter 1 -- IAPs inhibitor of apoptosis proteins -- IDH isocitrate dehydrogenase -- IDH1 isocitrate dehydrogenase 1 -- IDH2 isocitrate dehydrogenase 2 -- IFN interferon -- IGF-1 insulin-like growth factor-1 -- IGF-1R insulin growth factor-1 receptor -- IKZF1 Ikaros -- IKZF3 Aiolos -- IL-6 interleukin 6 -- IMiD immunomodulatory drugs -- IMA imatinib -- InS/GF Insulin/Growth Factor -- InsR insulin receptor -- IRF4 interferon regulatory factor 4 -- IRS-1 insulin receptor substrate 1 -- IκB inhibitors of nuclear factor-κB -- JAK Janus kinase -- JNKs Jun N-terminal kinases -- KIT stem cell growth factor receptor -- LEN lenalidomide -- LSAs lineage-specific antigens -- LTK leukocyte tyrosine kinase -- mAbs monoclonal antibodies -- MAPK mitogen-activated protein kinase -- MB medulloblastoma -- MCL mantle cell lymphoma -- MDS myelodysplastic syndromes -- MDSCs myeloid-derived suppressor cells -- MET met proto-oncogene -- MHC major histocompatibility complex -- MM multiple myeloma -- MMAE monomethyl auristatin E -- MPN myeloproliferative neoplasm -- MRP1 multidrug resistance associated protein -- mTOR mammalian target of rapamycin -- NFE2L2 nuclear factor, erythroid 2 like 2 -- NLSAs non-LSAs -- NRTK non-receptor tyrosine kinase -- NSCLC non-small cell lung cancer -- OS overall survival -- P-gp P-glycoprotein (ABCB1) -- PD-1 programmed cell death 1 -- PD-L1 programmed cell death 1 ligand 1 -- PARP1 poly(ADP-ribose) polymerase 1 -- PDGF platelet derived growth factor -- PFS progression-free survival -- PI3K phosphatidylinositol 3-kinase -- PIs proteasome inhibitors -- PKC protein kinase C -- PLCγ2 phospholipase c gamma 2 -- PLK Polo-like kinases -- PN proteostasis network -- POM pomalidomide -- PTCH1 patched 1 -- PTCL peripheral T-cell lymphoma -- RP 19S proteasome regulatory particle -- RTK receptor tyrosine kinase -- scDbs single chain diabodies -- scFv single-chain variable fragment -- SCLC small-cell lung cancer -- SHC src homology 2 domain containing transforming protein 1 -- SLAMF7 lymphocytic activation molecule F7 -- SLC28 solute carrier family 28 -- SLC29 solute carrier family 29 -- SLL small lymphocytic lymphoma -- SMO smoothened -- STAT signal transducer and activator of transcription -- SUFU hedgehog inhibitor suppressor of fused -- taFvs tandem single chain variable fragments -- TAMs tumor-associated macrophages -- Tcon conventional T cells -- TCR T-cell receptor -- TET ten eleven translocation -- THAL thalidomide -- TILs tumor-infiltrating lymphocytes -- TKIs tyrosine kinase inhibitors -- TME tumor microenvironment -- TML tumor mutational load -- TNF-α tumor necrosis factor α -- TNF tumor necrosis factor -- TRAIL tumor necrosis factor-related apoptosis-inducing ligand -- Treg regulatory T cells -- TRX thioredoxin -- UCK uridine-cytidine kinase -- UPP ubiquitin-proteasome pathway -- UPR unfolded protein response -- VEGF vascular endothelial growth factor -- XIAP X-linked inhibitor of apoptosis; Apoptosis -- Autophagy -- Epigenetic modulator -- Hedgehog inhibitor -- Immunotherapeutic agents -- Kinase inhibitor -- Metabolic modulator -- Proteasome inhibitors; Drug resistance in cancer cells -- Periodicals; Cancer -- Chemotherapy -- Periodicals; 616.994061
• DOI: 10.1016/j.drup.2019.100646
• Languages: English
• ISSNs: 1368-7646

Abstract

Abstract: For many decades classical anti-tumor therapies included chemotherapy, radiation and surgery; however, in the last two decades, following the identification of the genomic drivers and main hallmarks of cancer, the introduction of therapies that target specific tumor-promoting oncogenic or non-oncogenic pathways, has revolutionized cancer therapeutics. Despite the significant progress in cancer therapy, clinical oncologists are often facing the primary impediment of anticancer drug resistance, as many cancer patients display either intrinsic chemoresistance from the very beginning of the therapy or after initial responses and upon repeated drug treatment cycles, acquired drug resistance develops and thus relapse emerges, resulting in increased mortality. Our attempts to understand the molecular basis underlying these drug resistance phenotypes in pre-clinical models and patient specimens revealed the extreme plasticity and adaptive pathways employed by tumor cells, being under sustained stress and extensive genomic/proteomic instability due to the applied therapeutic regimens. Subsequent efforts have yielded more effective inhibitors and combinatorial approaches (e.g. the use of specific pharmacologic inhibitors with immunotherapy) that exhibit synergistic effects against tumor cells, hence enhancing therapeutic indices. Furthermore, new advanced methodologies that allow for the early detection of genetic/epigenetic alterations that lead to drug chemoresistance and prospective validation of biomarkers which identify patients that will benefit from certain drug classes, have started to improve the clinical outcome. This review discusses emerging principles of drug resistance to cancer therapies targeting a wide array of oncogenic kinases, along with hedgehog pathway and the proteasome and apoptotic inducers, as well as epigenetic and metabolic modulators. We further discuss mechanisms of resistance to monoclonal antibodies, immunomodulators and immune checkpoint inhibitors, potential biomarkers of drug response/drug resistance, along with possible new therapeutic avenues for the clinicians to combat devastating drug resistant malignancies. It is foreseen that these topics will be major areas of focused multidisciplinary translational research in the years to come.