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Table 1 Some anticancer treatments are subject to acquired resistance provoked by stromal factors derived from the disease-supporting TME

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 [43,44]
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]