Targeting tumour microenvironment by tyrosine kinase inhibitor

Abstract

Tumour microenvironment (TME) is a key determinant of tumour growth and metastasis. TME could be very different for each type and location of tumour and TME may change constantly during tumour growth. Multiple counterparts in surrounding microenvironment including mesenchymal-, hematopoietic-originated cells as well as non-cellular components affect TME. Thus, therapeutics that can disrupt the tumour-favouring microenvironment should be further explored for cancer therapy. Previous efforts in unravelling the dysregulated mechanisms of TME components has identified numerous protein tyrosine kinases, while its corresponding inhibitors have demonstrated potent modulatory effect on TME. Recent works have demonstrated that beyond the direct action on cancer cells, tyrosine kinase inhibitors (TKIs) have been implicated in inactivation or normalization of dysregulated TME components leading to cancer regression. Either through re-sensitizing the tumour cells or reversing the immunological tolerance microenvironment, the emergence of these TME modulatory mechanism of TKIs supports the combinatory use of TKIs with current chemotherapy or immunotherapy for cancer therapy. Therefore, an appropriate understanding on TME modulation by TKIs may offer another mode of action of TKIs for cancer treatment. This review highlights mode of kinase activation or paracrine ligand production from TME components and summarises the findings on the potential use of various TKIs on regulating TME components. At last, the combination use of current TKIs with immunotherapy in the perspectives of efficacy and safety are discussed.

Tyrosine Kinase Inhibitors in Cancer: Breakthrough and Challenges of Targeted Therapy

“…Stromal cells in TME exposed to RTKIs produce cytokines, hormones, or growth factors that modulate the response of the tumor to RTKIs. Thus, RTKIs targeting focal adhesion kinase (FAK), FGFR, c-MET, and VEGFR decrease the number of fibroblasts or their activation, and therefore their role in supporting growth of various tumors [64,65].…”

“…PDGFR and VEGFR inhibitors administered in small doses induce vascular normalization which improves drug distribution within the tumor. The depletion of pericytes and hypoxia caused by sunitinib treatment may increase the metastatic spread of tumor cells [64].…”

The design and development of covalent protein-protein interaction inhibitors for cancer treatment

“…Therefore, developing small molecule inhibitors to directly disrupt the MLL-menin interaction is a potential strategy for leukemia treatment [100,101]. Furthermore, while many cancers are driven by aberrant kinase activity, it is thought that targeting the PPIs that regulate the activity of a specific kinase is a more viable approach to develop selective kinase inhibitors than targeting the conserved ATP binding site of kinases directly [4,102,103]. For instance, the heat shock protein (Hsp90)-Cdc37 PPI promotes colorectal cancer.…”

Rationale of Immunotherapy in Hepatocellular Carcinoma and Its Potential Biomarkers

“…Targets of Sorafenib include VEGFR, PDGFR, and RAF kinases, hence exerting antitumor effects through anti-angiogenesis, antiproliferation, and pro-apoptosis [159]. The impact of mTKIs on the TME has also been discussed before [160][161][162]. Most studies demonstrated the immunomodulating properties of mTKIs, such as reduction of MDSCs and Treg [163][164][165][166], enhancing T and NK cells tumor infiltration and activation [167,168], and boosting antitumor immune response.…”