Although molecular-targeted drugs have been known to show high efficacy to lung cancer patients, they also have limitations due to acquiring resistance to the drug used. Recurrence of target tumors may therefore take place, which is a serious problem. It has been well recognized that genetic mutation is somehow induced in the cancer cells on which the molecular-targeted drug is effective and that consequently, the structure of the target molecule of the cancer cell is changed; thus the cancer cell acquires resistance. In addition to genetic mutation, it has recently been suspected that epithelial-to-mesenchymal transition (EMT) is another mechanism for cancer to acquire such resistance. However, the detailed relationship between EMT and drug resistance has not been elucidated, and medical treatments to overcome such problems have not been established.
[Outline of research results]
The present research team at Kanazawa University analyzed tumor tissues from patients with ALK-positive lung cancer that acquired resistance to crizonitib, a molecular-targeted drug. As a result, it was revealed that a part of the tumor lesion developed a genetic mutation while another part underwent EMT. It was therefore thought that genetic mutation(s) and EMT should be individually responsible for the resistance against the molecular-targeted drug.
Next generation molecular-targeted drugs that should overcome genetic mutation problems have already been used clinically, whereas no therapeutic means have been developed for the resistance due to EMT. The team investigated the mechanism for inducing cancer cell EMT. As a result, it was found that cancer cells acquired resistance to the molecular-targeted drug by transforming epithelial characteristics into mesenchymal ones, caused by reduction in the cancer cells of the expression of miR-200c (one of the microRNAs that regulate gene expression). Reduction of miR-200c expression augments the level of ZEB1, a transcription factor that induces EMT, and reduces the level of E-cadherin, a protein involved in cell adhesion.
Next, the team searched for compounds that could augment the expression of miR-200c to normal levels, in the hope that the resistance could be overcome by possible reverse-transition of mesenchymal cancer cells into epithelial ones. As a result, treatment with an HDAC (histone deacetylase) inhibitor, quisinostat, reversed the transformation of mesenchymal cancer cells into epithelial cells, which led to successful sensitization of the resultant cells to molecular-targeted drugs (Figure 2).
In addition, it was revealed in animal experiments that acquisition of cancer cell resistance to the molecular-targeted drug was evidently prevented by quisinostat treatment prior to the drug treatment.
From these results, sequential treatment with quisinostat, an HDAC inhibitor, followed by a next generation molecular-targeted drug may have a big potential for overcoming resistance to molecular-targeted drug by ALK-positive lung cancers due to genetic mutation and EMT (Figure 3).
Due to these results, it is now expected that patients with a cancer demonstrated to have EMT and resistance against targeted drugs may be, by overcoming such resistance, completely cured or may have a significant delay of cancer recurrence by sequential treatment with an HDAC inhibitor and a next generation molecular-targeted drug.
The team will now investigate the selection of the best HDAC inhibitor in terms of efficacy and adverse effects as well as the clinical examination of therapy in combination with next generation molecular-targeted drugs.