Strategies to overcome resistance to epidermal growth factor receptor monoclonal antibody therapy in metastatic colorectal cancer

Table 1 Components of the epidermal growth factor receptor signaling pathway and their abnormalities in colorectal cancer

Component(gene/protein)	Defect in CRC	Frequency in CRC
EGFR/EGFR	Protein expression	25%-90%
	Mutation	Rare
	Increased copy number	0%-50%
K-ras/K-Ras	Activating mutation	30%-40%
	(exon 2, codon 12, 13, exon 3/4, codon 61, 117, 146)
N-ras/N-Ras	Activating mutation	3%-5%
	(exon 1, codon 12, 13, exon 2, codon 61)
B-Raf/BRAF	Activating mutation (V600E)	10%-15%
PIK3CA/PI3KCA	Activating mutation (exons 9 and 20)	15%-18%
PTEN/PTEN	Loss of protein expression	13%-19%
	Mutation
	Loss of heterozygosity

CRC: Colorectal cancer; EGFR: Epidermal growth factor receptor.

Table 2 RAF, MEK and PI3K/mTOR inhibitors presently in the status of clinical trial in colorectal cancer

Drug	Target	Manufacturer	Phase	Indication
Sorafenib	BRAF	Bayer	II	Colon cancer (combination with cetuximab)
PLX4032	BRAFV600E	Plexxikon	I	Melanoma, colon cancer
XL281	BRAF	Exelixis	I	Solid tumors
GSK1120212	MEK	GlaxoSmithKline	I	Solid tumors, Lymphoma
AZD6244	MEK	AstraZeneca	II	Colon cancer (combination with capecitabine)
AS703026	MEK	EMD Serono	I	Solid tumors
GDC-0973	MEK	Genentech	I	Solid tumors
RO5126766	MEK	Hoffman-La Roche	I	Solid tumors
TAK-733	MEK	Millenium	I	Solid tumors
RDEA119	MEK	Ardea Biosciences	I	Solid tumors
BGT226	PI3K	Novartis	I/II	Solid tumors, Her2 positive Breast Cancer
XL147	PI3K	Exelixis	I	Solid tumors, Lymphoma
XL765	PI3K	Exelixis	I	Solid tumors
BEZ235	PI3K	Novartis	I	Solid tumors
GDC-0941	PI3K	Genentech	I	Solid tumors
PX-866	PI3K	ProIX	I	Solid tumors
SF1126	PI3K	Semafore	I	Solid tumors
Everolimus	mTOR	Novartis	II	Colon cancer (combination with cetuximab)