From: New horizons in tumor microenvironment biology: challenges and opportunities
Therapeutics | Cancer type | Targeting mechanism | Resistance mechanism | Reference |
---|---|---|---|---|
Doxorubicin | Multiple myeloma | Generate DNA intercalation; inhibit topoisomerase II | Stroma-induced resistance | [41] |
PD184352 | BRAF-mutant melanoma | Block MAPK pathway as an ATP non-competitive MEK1/2 inhibitor | Macrophage-derived TNF-α promotes microphthalmia transcription factor expression in BrafV600E melanoma cells, reducing caspase-3 cleavage under anoikis conditions | [36] |
External beam radiation therapy | Anaplastic thyroid cancer | Generate DNA intercalation; inhibit topoisomerase II | Stroma-induced resistance; plays an important role in mortality of thyroid cancer | [42] |
Mitoxantrone and docetaxel | Prostate cancer | Interrupt microtubule depolymerisation/disassembly; generates DNA strand breaks, inhibit topoisomerase II | Stroma-induced resistance through secretion of multiple soluble factors, with WNT16B as a major contributor | [39] |
Doxorubicin | Burkitt’s lymphoma | Generate DNA intercalation; inhibit topoisomerase II | Stroma-induced resistance; paracrine factors including IL-6 and Timp-1 from thymic endothelial cells in the tumor microenvironment modulate lymphoma cell survival following chemotherapy | [37] |
Doxorubicin and cyclophosphamide (AC regimen) | Breast cancer | Generate DNA intercalation; inhibits topoisomerase II and interferes with DNA replication | Stroma-induced resistance; chemotherapeutic agents trigger a stromal reaction leading to TNF-α production by endothelial and other stromal cells | [40] |
Vemurafenib (PLX4032) | BRAFV600E-mutant melanoma; BRAF-mutant colorectal cancer and glioblastoma | Interrupts the B-Raf/MEK step on the B-Raf/MEK/ERK pathway | Stroma-induced resistance; resistance to RAF inhibitors is induced by hepatocyte growth factor secreted from tumor-adjacent stromal cells | |
Ruxolitinib (INCB018424) | JAK2V617F-mutant myeloproliferative disorders and high-risk myelofibrosis (a type of bone marrow cancer) | Inhibits Janus kinase inhibitor with selectivity for subtypes JAK1 and JAK2 of this enzyme | Stroma-induced resistance; humoral factors secreted by stromal cells protect myeloproliferative neoplasms clones against JAK2 inhibitor therapy | [45] |
Erlotinib and gefitinib | Metastatic lung, colorectal, pancreatic, or head and neck cancers | Inhibits the epidermal growth factor receptor (EGFR), can stimulate apoptosis and differentiation of cancer cell that lack EGFR | Substantial stroma-induced resistance; clinical responses to EGFR tyrosine kinase inhibitors and monoclonal antibodies are now tempered by the increasing number of de novo and acquired resistance mechanisms, the latter contributed by stroma | [27] |
Afatinib | Metastatic non-small cell lung cancer, breast cancer, and other EGFR/Her2-driven cancers | Irreversibly inhibits EGFR and HER2 kinases | Stromal expression of fibroblast growth factor (FGF) 2 and the FGFR1 is upregulated, allowing survival of afatinib-resistant cancer cells | [46] |