Table 1.

Alternative receptor tyrosine kinases observed to form heterodimers with members of the EGFR family.

EGFR family member	Interacting RTK	Detection method	Sufficient controls	Sufficient loading	Functional outcome of heterodimer formation	Tissue	References
EGFR	FGFR2	co-IP	No	No	Resistance to FGFR2 inhibitor (AZD4547), possibly through ERK activation.	SNU16 and KATOIII gastric cancer cell lines	Chang et al., 2015
	AXL	Cross-linking co-IP	Yes	Yes	Ligand induced, EGFR mediated phosphorylation of AXL. Increased Akt signaling, cell motility and resistance to erlotinib.	MDA-MB-231 and MCF-7 breast cancer cell lines	Meyer et al., 2013
		MS	Yes	Yes	HGF-induced EGFR inhibition, resulting in increased interaction and activation of AXL.	SCC9 HNSCC cell line	Gusenbauer et al., 2013
		co-IP	No	Yes
	EPHA2	MS	Yes	Yes	HGF-induced EGFR inhibition, resulting in increased interaction and activation of EphA2.	SCC9 HNSCC cell line	Gusenbauer et al., 2013
		co-IP	No	Yes
	IGF1R	co-IP	Yes	No	Heterodimer induced by both IGF-1 and EGF. Increased IGF-1 induced ERK activation.	Normal mammary epithelial cells	Ahmad et al., 2004
	MET	MS	Yes	Yes	HGF-induced EGFR inhibition through ERK signaling. Resistance to gefitinib.	SCC9 HNSCC cell line	Gusenbauer et al., 2013
		co-IP	Yes	Yes	Transactivation of EGFR by MET in MET amplified cells. Depletion of EGFR inhibited ERK and AKT activation, promoting apoptosis.	EBC-1 and H1993 non-small lung cancer cell lines	Tanizaki et al., 2011
		co-IP	No	Yes	EGF or TGFα induced unidirectional transactivation of MET by EGFR.	HepG2, AKN-1, and HuH6 human hepatoma cell lines. A431 human epidermoid carcinoma cell line	Jo et al., 2000
		co-IP	Yes	Yes	c-Src dependent transactivation of MET by EGFR, in the absence of HGF. Promotes cell proliferation and resistance to EGFR inhibitors.	SUM229 breast cancer cell line	Mueller et al., 2010
	PDGFR	co-IP	No	Yes	Heterodimers detected, no function attributed.	Malignant peripheral nerve sheath tumor samples	Perrone et al., 2009
		Cross-linking co-IP	Yes	Yes	c-Src dependent transactivation of EGFR by PDGFRβ, following PDGF stimulation. Promotes ERK activation.	Rat aortic vascular smooth muscle cells	Saito et al., 2001
		co-IP	Yes	No	Ligand independent transactivation of PDGFRβ by EGFR observed in EGFR over-expressing cells.	COS-7 and Hs27 cell lines	Habib et al., 1998
	RET	co-IP	Yes	Yes	EGF dependent transactivation of RET by EGFR. Promotion of cell proliferation.	PCCL3 papillary thyroid carcinoma cell line	Croyle et al., 2008
ErbB2	MET	co-IP	Yes	Yes	Transactivation of ErbB2 by MET in MET amplified cells. Depletion of ErbB2 inhibited ERK and AKT activation, promoting apoptosis, and STAT3 activation, inhibiting migration.	EBC-1 and H1993 non-small lung cancer cell lines	Tanizaki et al., 2011
	AXL	Cross-linking co-IP	Yes	Yes	Inferred resistance to lapatinib.	MDA-MB-231 and MCF-7 breast cancer cell lines	Meyer et al., 2013
	NTRK1	co-IP	Yes	Yes	NGF induced transactivation of ErbB2 by NTRK1, promoting ERK activation and proliferation.	SKBR3 breast cancer cell line	Tagliabue et al., 2000
	IGF-1R	co-IP	Yes	Yes	Transactivation of ErbB2 by IGF-1R. Interaction induced by heregulin and IGF-1.	C4HD and MCF-7 breast cancer cell lines	Balañá et al., 2001
		co-IP	No	Yes	Transactivation of ErbB2 by IGF-1R, leading to trastuzumab resistance.	SKBR3 breast cancer cell line	Nahta et al., 2005
		co-IP	No	Yes	Hetero-dimer present in trastuzumab resistant cells. Proposed hetero-trimer with ErbB3.	SKBR3 and BT474 breast cancer cell line	Huang et al., 2010
		co-IP	Yes	Yes	Dual targeting of ErbB2:IGF-1R heterodimer increases sensitivity to trastuzumab.	SKBR3 and BT474 breast cancer cell line	Browne et al., 2011
ErbB3	RET	PLA, co-IP (transfected ErbB3)	Yes	Yes	May promote vandetanib resistance.	1765–92 Myxoid cell line	Safavi et al., 2016
	AXL	Cross-linking co-IP	Yes	Yes	Inferred resistance to ErbB3 targeted therapy.	MDA-MB-231 and MCF-7 breast cancer cell lines	Meyer et al., 2013
	MET	co-IP	Yes	Yes	Transactivation of ErbB3 by MET, in MET amplified cells. Depletion of ErbB3 inhibited ERK and AKT activation, promoting apoptosis.	EBC-1 and H1993 non-small lung cancer cell lines	Tanizaki et al., 2011
		co-IP	No	Yes	Transactivation of ErbB3 by MET in MET amplified cells. Promotes PI3K pathway activation and resistance to gefitinib	HCC827 NSCLC cell line	Engelman et al., 2007
	IGF-1R	co-IP	No	Yes	Promotes trastuzumab resistance, proposed hetero-trimer with ErbB2.	SKBR3 and BT474 breast cancer cell line	Huang et al., 2010
	FGFR2	co-IP	No	No	Resistance to FGFR2 inhibitor (AZD4547), possibly through ERK activation.	SNU16 and KATOIII gastric cancer cell lines	Chang et al., 2015