Method for treating cancer having resistance to kinase inhibitors

Abstract

Resistance to kinase inhibitors is the biggest disorder of effective treatment for cancer patients. The recent research shows that the occurrence of the drug resistance may not only be generally considered by people to be explained by the existing drug-resistant subcloning drug selection, but also be caused by the generation of a small amount of drug-resistant cells (DTC) and entering a slow circulation state through the cells, so that the drug resistance has a resistance effect on treatment at the beginning. Therefore, a novel promising method should be adopted for the DTCs to prevent secondary drug resistance to kinase inhibitors. At present, the inventor has proved that inhibition of farnesyl transferase (but not geranyl geranyl transferase) can prevent the drug resistance in different carcinogenic environments. Particularly, the inventor determines the curative effect of a farnesyl transferase inhibitor (namely tipifarnib) and erlotinib which are jointly used in several EGFR (epidermal growth factor receptor) mutant cell lines in vitro. It is shown that the combination can effectively eliminate all drug-resistant cells and completely prevent the occurrence of drug-resistant cloning. It is interesting that similar results are also observed in other oncogenic models, such as ALK-translocated lung cancer cells or BRAF-mutated melanoma cells. Therefore, the present invention relates to the use of farnesyltransferase inhibitors in the treatment of kinase inhibitor resistant cancers.

Description

technical field [0001] The present invention relates to the field of medicine, in particular oncology. Background technique [0002] Lung cancer is the leading cause of cancer deaths worldwide 1 . Metastatic non-small cell lung cancer (NSCLC) has recently benefited from two consecutive breakthroughs: the identification of oncogene drivers, such as EGFR mutations, leading to the development of targeted therapies, and the understanding of the cancer immune cycle, leading to immune checkpoints Development of inhibitors. [0003] First-generation EGFR-tyrosine kinase inhibitors (EGFR-TKIs) such as erlotinib or gefitinib are effective treatments for NSCLC with EGFR-activating mutations 2 . However, despite the 70% response rate, patients typically relapse within a median time of 12 months due to the development of drug resistance. Mechanisms of acquired resistance include EGFR T790M Mutations, including MET 3 or HER2 4 Activation of alternative pathways, including epithel...

AI Technical Summary

Problems solved by technology

However, we still lack accurate in vivo phenotypic and molecular characterization of this specific state, which is a prerequisite for the development of new therapies

Images