A Targeted Therapy–Driven Tumor Secretome Underlies Drug Resistance

Although kinase inhibitors targeting oncogenic drivers such as BRAF, ALK, and EGFR often initially result in partial tumor regressions, most patients develop resistance and experience tumor progression. Preexisting intrinsically resistant cancer cells have been proposed to contribute to the development of clinical drug resistance and tumor relapse; however, the response of this small population of resistant cells to drug-induced changes in the tumor microenvironment remains poorly characterized. Using admixed cultures of drug-sensitive and drug-resistant melanoma cells, Obenauf and colleagues found that treatment with the BRAF inhibitor vemurafenib enhanced the outgrowth and infiltration of resistant cells within regressing tumors and resulted in increased metastasis. Intriguingly, similar growth acceleration of resistant cells was observed in multiple melanoma models driven by distinct clinically relevant resistance mechanisms as well as in lung adenocarcinoma models in response to treatment with the ALK inhibitor crizotinib or the EGFR inhibitor erlotinib. This growth-promoting effect was mediated by the secretion of signals by drug-sensitive cancer cells into the regressing tumor microenvironment in response to targeted therapy, which increased the survival of sensitive cells and augmented the proliferation and migration of the resistant subpopulation. Analysis of gene expression profiles revealed that this therapy-induced secretome was driven by downregulation of the transcription factor FOS-related antigen 1 (FRA1), a downstream effector of the ERK pathway, in drug-sensitive cells during RAF inhibitor treatment, and stimulated a transcriptional program in drug-resistant cells characterized by hyperactivation of the PI3K–AKT pathway. Consistent with this finding, combined inhibition of the MAPK and PI3K–AKT–mTOR pathways diminished the outgrowth of vemurafenib-resistant BRAF-mutant melanoma cells both in vitro and in vivo. These results indicate that targeted kinase inhibitors paradoxically generate a tumor-promoting microenvironment that facilitates drug resistance and suggest therapeutic strategies to target this secretome and limit tumor relapse.

Obenauf AC, Zou Y, Ji AL, Vanharanta S, Shu W, Shi H, et al. Therapy-induced tumour secretomes promote resistance and tumour progression. Nature 2015 Mar 25 [Epub ahead of print].