Targeting Tyrosine Kinases in Ovarian Cancer: Small Molecule Inhibitor and Monoclonal Antibody, Where Are We Now?

Abstract

Ovarian cancer is one of the most lethal gynaecological malignancies worldwide. Despite high success rates following first time treatment, this heterogenous disease is prone to recurrence. Oncogenic activity of receptor tyrosine kinases is believed to drive the progression of ovarian cancer. Here we provide an update on the progress of the therapeutic targeting of receptor tyrosine kinases in ovarian cancer. Broadly, drug classes that inhibit tyrosine kinase/pathways can be classified as small molecule inhibitors, monoclonal antibodies, or immunotherapeutic vaccines. Small molecule inhibitors tested in clinical trials thus far include sorafenib, sunitinib, pazopanib, tivantinib, and erlotinib. Monoclonal antibodies include bevacizumab, cetuximab, pertuzumab, trastuzumab, and seribantumab. While numerous trials have been carried out, the results of monotherapeutic agents have not been satisfactory. For combination with chemotherapy, the monoclonal antibodies appear more effective, though the efficacy is limited by low frequency of target alteration and a lack of useful predictive markers for treatment stratification. There remain critical gaps for the treatment of platinum-resistant ovarian cancers; however, platinum-sensitive tumours may benefit from the combination of tyrosine kinase targeting drugs and PARP inhibitors. Immunotherapeutics such as a peptide B-cell epitope vaccine and plasmid-based DNA vaccine have shown some efficacy both as monotherapeutic agents and in combination therapy, but require further development to validate current findings. In conclusion, the tyrosine kinases remain attractive targets for treating ovarian cancers. Future development will need to consider effective drug combination, frequency of target, and developing predictive biomarker.

Keywords: cancer vaccine; kinase inhibitors; ovarian cancer; platinum resistance; recurrent cancers; tyrosine kinases.

Figure 1

Mechanisms of oncogenic RTK activation. (a) Visual representation of autocrine activated RTK signalling. Increased ligand production by cancer cells or the tumour microenvironment causes activation of RTK signalling, leading to increased kinase activity and phosphorylation of the C-terminal tail of the receptor. (b) Chromosomal rearrangement results in the creation of a hybrid fusion oncoprotein composing partly of the TK and fusion partner. These RTK fusion partners are often cytoplasmic or membrane bound proteins depending on the position of the genomic cut-off point. The rearrangement results in deletion of regulatory domains, which then causes tyrosine kinase activation. (c) Duplication of tyrosine kinase domain could result in the formation of an intramolecular dimer and activation of RTK, in the absence of ligands. (d) Diagrammatic illustration of probable gain-of-function mutations in several RTK subdomains. Mutations in these regions lead to constitutive activation of the RTK, more often than not in the absence of ligands. (e) Visual representation of RTK genomic amplification is frequently a consequence of the genomic amplification of RTK genes, resulting in the increase of local concentrations of RTKs.