Abstract
Mismatch-repair-deficient colorectal cancers often contain kinase-activating V600E BRAF mutations, but no clinical utility has yet been demonstrated in this setting for monotherapy using oral braf kinase inhibitors such as vemurafenib or dabrafenib. Recent studies have indicated that tumour resistance to braf inhibition is mediated by upregulated epidermal growth factor receptor (egfr) signalling, disruption of which is a routine treatment strategy in KRAS wild-type colorectal cancer. In this report, we describe the clinical course of a heavily pretreated patient who elected to receive off-label dual-targeted braf- and egfr-inhibitory therapy with good tolerance and apparent clinical benefit.
Highlights
Melanomas containing missense V600E BRAF mutations may respond dramatically to braf kinase inhibitors such as vemurafenib[1] or dabrafenib[2], but the survival benefit has proved to be relatively modest[3], in part reflecting rapid selection for resistance[4] because of braf inhibitor–induced upregulation of wild-type signalling pathways[5,6,7,8], such as those regulated by platelet-derived growth factor[9] or hepatocyte growth factor[10]
Fewer than 10% of BRAFV600E-mutated colorectal cancers have responded to braf kinase inhibitor monotherapy in early-phase trials[14], raising the possibility that effective treatment may require blockade of one or more additional pathways[15]
Because recent laboratory studies have confirmed that de novo resistance to braf inhibitors in BRAFV600E-mutated colorectal cancer is caused by egfr signalling[19,20], we hypothesised that dual blockade of the braf and egfr pathways might be therapeutically useful, as has been suggested by preclinical data[15]
Summary
Melanomas containing missense V600E BRAF mutations may respond dramatically to braf kinase inhibitors such as vemurafenib[1] or dabrafenib[2], but the survival benefit has proved to be relatively modest[3], in part reflecting rapid selection for resistance[4] because of braf inhibitor–induced upregulation of wild-type signalling pathways[5,6,7,8], such as those regulated by platelet-derived growth factor[9] or hepatocyte growth factor[10]. Activating V600E BRAF mutations are present in up to 10% of unselected colorectal cancers, with this proportion rising to more than 60% in tumours with microsatellite instability because of reduced expression of mismatch repair enzymes[11]. These BRAF mutations are mutually exclusive with oncogenic KRAS mutations[12], but imply a similar treatment-refractory prognosis[13]. Fewer than 10% of BRAFV600E-mutated colorectal cancers have responded to braf kinase inhibitor monotherapy in early-phase trials[14], raising the possibility that effective treatment may require blockade of one or more additional pathways[15]. We report an end-stage colorectal cancer patient benefiting from combination noncytotoxic drug therapy simultaneously targeting the egfr and braf signalling pathways
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