Growth factor driven resistance to anticancer kinase inhibitors
Hepatocyte growth factor reactivates the MAPK and Akt signalling pathways to confer drug resistance
- Date : 14 Aug 2012
- Topic : Personalised medicine
Two new studies, published in Nature, have independently revealed that growth factors contribute to the innate drug resistance of many cancer types. The first growth factor featured in such regard is hepatocyte growth factor (HGF), which reactivates the MAPK and Akt signalling pathways to confer drug resistance. Mina Razzak highlighted these two studies in the August issue of the Nature Reviews Clinical Oncology. The first article by R Straussman et al. covers innate resistance to RAF inhibitors through HGF secretion, and the second one by TR Wilson et al. a widespread potential for growth factor driven resistance to kinase inhibitors.
A much larger panel of growth factors might also contribute to drug resistance
The first study was led by Todd Golub, and tested the hypothesis that stromal cells not only promote tumour growth and metastasis but have a role in drug resistance. His group treated a range of tumour cell lines, 45 in total, alone or co-cultured with 23 different types of stromal cells with 35 commonly used cancer drugs. The results were marked: drugs otherwise capable of killing cancer cells alone were unable to do so when the cancer cells were co-cultured with stromal cells. Although different stromal cells had differing effects, resistance to targeted therapies was more pronounced than resistance to cytotoxic agents.
The researchers then tried to identify which factor or factors in particular were responsible for conferring resistance. Using BRAF-mutant melanoma cell lines as their model and PLX4720, a RAF inhibitor, they were able to identify HGF as the likely candidate. Although HGF and its receptor MET have been implicated in melanoma growth, neither were known to have a role in resistance to RAF inhibition. Furthermore, the researchers deduced that HGF activates the MAPK and Akt signalling pathways to override the tumour suppression caused by RAF inhibition. Looking at patient-derived samples, the investigators found that patients whose stromal cells secreted HGF had a poorer response to treatment. Overall, these results suggest that combining targeted therapy with HGF or MET inhibition might be a worthwhile endeavour.
This premise was supported by the work of another group, which showed that inhibition of MET blocked the HGF-mediated rescue in a BRAF-mutant xenograft model. The group, led by Jeff Settleman, identified HGF, EGF and FGF, as capable of rescuing a range of cancer cells that express mutationally activated kinases from growth inhibition by targeted therapy. The growth factors activate redundant pathways to rescue the cell from therapy, just as HGF activates the MAPK and Akt pathways. Indeed, patients with cancer might benefit from the profiling of their kinase expression patterns. Currently, efforts are underway to explore a much larger panel of growth factors that might also contribute to resistance.
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