Table 1.

Possible mechanisms of resistance to selective BRAF inhibitors and potential therapeutic combinations.

Level of resistance	Genetic mutation/alteration	Status of ERK pathway	Potential combination therapy	Reference
Upstream in the MAPK pathway	NRAS mutation (e.g. G12R, Q61K)	Dependent	BRAFi + MEKi	[Adjei et al. 2008; McArthur et al. 2011; Nazarian et al. 2010]
	PDGFRβ upregulation	Independent	PDGFRβ inhibitor ± BRAFi	[Corcoran et al. 2011; Nazarian et al. 2010]
			BRAFi + IGF1Ri
	Other RTK upregulation (e.g. IGF1R signalling)	Independent	BRAFi + PI3K/AKT/dual mTORi	[Corcoran et al. 2011; Villanueva et al. 2010]
At the RAF level	BRAF amplification	Dependent	BRAFi + MEKi	[Corcoran et al. 2010; Little et al. 2011]
	Elevated CRAF activity	Dependent	BRAFi + MEKi or CRAFi/nonselective RAFi	[Johannessen et al. 2010] [Montagut et al. 2008; Johannessen et al. 2010]
	Increased COT/Tpl2 levels (also acts downstream in the MAPK pathway)	Dependent	BRAFi + MEKi
Downstream in the MAPK pathway	MEK1 mutation (e.g. P124L, P124S, C121S)	Dependent	BRAFi and MEKi for P124L mt (not C121S)	[Corcoran et al. 2011; Emery et al. 2009; McArthur et al. 2011; Wagle et al. 2011]
Bypass pathway signalling	PTEN loss	Independent	BRAFi/MEKi + PI3K/mTORi	[Nathanson et al. 2011; Paraiso et al. 2011]
	PI3K-AKT pathway activation	Independent	BRAFi/MEKi + PI3K/AKT/mTORi
			BRAF/MEKi + PI3K/AKTi
	AKT3 mutation	Independent	BRAFi + IGF1Ri or PI3K/AKTi	[Jiang et al. 2011]
	IGF1R signalling	Independent	BRAFi + mTORi	[Shao and Aplin, 2010]
	CDK4 mutation/cyclin D1 amplification	Independent	BRAFi/MEKi + imatinib	[Villanueva et al. 2010]
	Co-overexpression of KIT/CDK4	Independent		[Smalley et al. 2008b, 2008a]

BRAFi, selective v-raf murine sarcoma viral oncogene homolog B1 inhibitor; CDK4, cyclin-dependent kinase 4; ERK, extracellular signal-regulated kinase; IGF1R, insulin-like growth factor 1 receptor; MAPK, mitogen-activated protein kinase; MEKi, MEK inhibitor; mTORi, mammalian target of rapamycin inhibitor; PDGFRβ, platelet-derived growth factor receptor β; PI3K, phosphoinositide 3-kinase; PTEN, phosphatase and tensin homolog; RTK, receptor tyrosine kinase.