Editors' ChoiceCancer

Sending survival signals

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Sci. Signal.  21 Apr 2015:
Vol. 8, Issue 373, pp. ec102
DOI: 10.1126/scisignal.aab3703

Therapies that specifically target aberrantly activated signaling proteins within cancer cells inevitably result in the development of resistant cells, which typically leads to rapid disease progression. Obenauf et al. introduced mixed populations of drug-sensitive cancer cells (BRAF-driven melanoma or ALK- or EGFR-driven lung adenocarcinoma) and labeled, resistant derivatives of the same cancer cell in mice and found that therapeutic treatment that inhibited the activated kinase specifically induced regression of the sensitive cells, but promoted the proliferation of the resistant cells. Additionally, in mice with subcutaneous tumors of sensitive cells, drug treatment caused resistant cells that were injected into the blood to extravasate and migrate into the tumor, suggesting that the sensitive cells produce signals in response to the drug that attract resistant cells. Indeed, conditioned medium from drug-treated melanoma or lung adenocarcinoma cell lines stimulated proliferation and enhanced migration of the respective resistant counterparts. Transcriptional analysis indicated an overlap in the differentially regulated genes encoding secreted proteins (secretome) from the drug-treated melanoma and lung adenocarcinoma cells. Integration of transcriptome data at 6 hours with the transcription factor binding sites enriched in the promoters of the secretome that were regulated 48 hours after drug exposure identified the transcription factor FRA1, which is stimulated by the extracellular signal–regulated kinase (ERK) pathway. Drug exposure reduced the abundance of FRA1 in sensitive but not resistant cells, and biopsies from patients before and after treatment with a RAF inhibitor exhibited reduced abundance of FRA1 after treatment. Conditioned medium from sensitive cells in which FRA1 was knocked down produced similar proliferation- and migration-inducing effects as medium from sensitive cells exposed to drug. Compared with coinjection of vector-expressing sensitive cells, coinjection of the FRA1-knockdown cells with resistant cells resulted in increased growth of tumors of resistant cells and attraction of resistant cells from the circulation to the FRA1-knockdown tumor. Analysis of actively translated RNAs and of protein abundance from the resistant cells in a tumor comprised of coinjected sensitive and resistant cells indicated activation of the phosphoinositide 3-kinase (PI3K)–AKT pathway after drug treatment. This pathway is also a known target of multiple secreted factors produced by the sensitive cells in response to targeted therapy. Combination therapy with drugs that inhibited PI3K-AKT or its downstream target (the kinase mTOR) along with the drug targeting BRAF reduced the growth-promoting effects of the therapy-induced secretome in conditioned medium and reduced growth of the resistant cells in tumors in coinjected mice. Thus, therapy-induced transcriptional changes in the drug-sensitive cells leads to the secretion of factors that promote survival signaling in drug-resistant cells.

A. C. Obenauf, Y. Zou, A. L. Ji, S. Vanharanta, W. Shu, H. Shi, X. Kong, M. C. Bosenberg, T. Wiesner, N. Rosen, R. S. Lo, J. Massagué, Therapy-induced tumour secretomes promote resistance and tumour progression. Nature 520, 368–372 (2015). [PubMed]