Drug resistance invariably limits the clinical efficacy of targeted therapy with kinase inhibitors against cancer. Scientists from Memorial Sloan Kettering Cancer Center have identified a new mechanism of the drug resistance in cancer treatment. A bunch of resistance cells are found to response to the huge changes in the micro-environment. The deep understanding of this process may help to promote the efficacy of targeted anti-cancer drugs. This study was published in Nature.

Kinase inhibitors such as vemurafenib, erlotinib or crizotibib have shown clinical efficacy in melanoma with BRAF mutations, or in lung adenocarcinoma with EGFR mutations or ALK translocations, respectively. Although complete responses are rare, the vast majority of patients show partial tumour regression or disease stabilization. However, drug resistance invariably develops, and most patients progress within 6-12 months, representing a common complication of targeted therapies that hampers long-term treatment success.

In this study, researchers show that targeted therapy with BRAF, ALK or EGFR kinase inhibitors induces a complex network of secreted signals in drug-stressed human and mouse melanoma and human lung adenocarcinoma cells. This therapy-induced secretome stimulates the outgrowth, dissemination and metastasis of drug-resistant cancer cell clones and supports the survival of drug-sensitive cancer cells, contributing to incomplete tumour regression.

The tumour-promoting secretome of melanoma cells treated with the kinase inhibitor vemurafebib is driven by down-regulation of the transcription factor FRA1. In situ transcriptome analysis of drug-resistant melanoma cells responding to the regressing tumour microenvironment revealed hyperactivation of several signaling pathways, most prominently the AKT pathway.

Thus, therapeutic inhibition of oncogenic drivers induces vast secretome changes in drug-sensitive cancer cell, paradoxically establishing a tumour micro-environment that supports the expansion of drug-resistant clones, but is susceptible to combination therapy.