The haves and the have nots

Alderton, Gemma K.

doi:10.1038/nrc3330

Research Highlight
Published: 24 July 2012

Tumour microenvironment

The haves and the have nots

Gemma K. Alderton

Nature Reviews Cancer volume 12, page 505 (2012)Cite this article

1207 Accesses
1 Citations
Metrics details

Subjects

Access through your institution

Buy or subscribe

Using co-culture experiments, Straussman and colleagues assessed how 23 human stromal cell lines affected the sensitivity of 45 human cancer cell lines to 35 anticancer drugs. They found that BRAF-V600E melanoma cells became resistant to the BRAF inhibitor PLX4720 when cultured with fibroblasts. The presence of hepatocyte growth factor (HGF) in conditioned medium from these fibroblasts correlated with resistance. Moreover, the proportion of HGF⁺ melanoma-associated stromal cells correlated with a poorer response to treatment with BRAF inhibitors than non-HGF⁺ samples of human BRAF-V600E melanoma. The inhibition of HGF or MET (the HGF receptor, which was also activated in HGF⁺ samples) resensitized melanoma cell lines to BRAF inhibitors, indicating that paracrine HGF–MET signalling mediates this innate resistance. Both the MEK–ERK and PI3K–AKT pathways were activated when BRAF-V600E melanoma cells were treated with HGF; other ligands activated either ERK or AKT, but these did not abrogate drug sensitivity, indicating that both pathways need to be activated to confer resistance. Finally, the authors found evidence of autocrine HGF–MET signalling in non-melanoma BRAF-V600E-mutant cancer cell lines, and combined BRAF and MET inhibition had synergistic effects in two such cell lines.

HGF–MET signalling is an important determinant of therapeutic responses

This is a preview of subscription content, access via your institution

Access options

Access through your institution

Buy this article

Purchase on SpringerLink
Instant access to the full article PDF.

USD 39.95

Prices may be subject to local taxes which are calculated during checkout

ORIGINAL RESEARCH PAPERS

Straussman, R. et al. Tumour micro-environment elicits innate resistance to RAF inhibitors through HGF secretion. Nature 4 Jul 2012 (doi:10.1038/nature11183)
Wilson, T. R. et al. Widespread potential for growth-factor-driven resistance to anticancer kinase inhibitors. Nature 4 Jul 2012 (doi:10.1038/nature11249)
Kentsis, A. et al. Autocrine activation of the MET receptor tyrosine kinase in acute myeloid leukemia. Nature Med. 18, 1118–1122 (2012)
Article CAS Google Scholar

Download references

Authors