EP4054579A1 — Methods for the treatment of cancers that have acquired resistance to kinase inhibitors

USPTO Abstract

Resistance to kinase inhibitors exemplifies the greatest hindrance to effective treatment of cancer patients. Recent studies have suggested that the onset of said resistance might not only be explained by a drug selection of pre-existing resistant sub-clones as it what was generally assumed, but may also arise de novo from a small population of drug-tolerant cells (DTC) that initially resists the treatment by entering a slow cycling state. Thus, targeting these DTC should be a new promising approach to hamper the emergence of secondary resistance to kinase inhibitors. The inventors now demonstrate that farnesyltransferase (but not geranylgeranyl transferase) inhibition can prevent the emergence of said resistance in different oncogenic contexts. In particular, the inventors determined in vitro the efficacy of farnesyltransferase inhibitor (i.e. Tipifarnib) in combination with erlotinib in several EGFR-mutated cell lines. They showed that the combination efficiently eliminated all drug tolerant cells, and fully prevented the emergence of resistant clones. Interestingly, similar results were observed in other oncogenic models such as ALK-translocated lung cancer cells or BRAF-mutated melanoma cells. Thus the present invention relates to use of farnesyl transferase inhibitors for the treatment of cancers that have acquired resistance to kinase inhibitors.