Table 3.

Rational synergies under exploration with EGFR inhibitors.

	Preclinical co-targets	Trials
Target	Rationale	Phase
VEGF/VEGFR	VEGF signaling confers resistance by activating PI3K-Akt [137,138]	II
ADAM17	Inhibition of sheddases prevents release of ligand [8,115]	I
ErbB3	Antibody to ErbB3 blocks survival signals to PI3K-Akt [20]	I
c-Met, IGF-1R	Antibodies and TKIs prevent transphosphorylation and PI3K-Akt signaling [20,220]	I
STAT3	Decoy oligonucleotide blocks STAT3-mediated activation of transcription, resistance to apoptosis [169]	II
mTOR	Synergistic effects in preclinical models [227], tolerated combination in mCRC	I
PI3K	Synergistic with EGFR inhibition, PI3K activation via other surface receptors (ErbB3, IGF-R1, Met) protects from apoptosis [55,228]	I
Src	Dasatinib, a multitargeted kinase inhibitor, blocks Src activity and increases efficacy of Cetuximab. Src activates signaling of ErbB family receptors [127]

ADAM: a disintegrin and metalloprotease; Akt: v-akt murine thymoma viral oncogene homolog; ERB3: v-erb-b oncogene homolog 3; mCRC: metastatic colorectal cancer; mTOR: mammalian target of rapamycin; PI3K: phosphinositol 3 kinase; PTEN: phosphatase and tensin homolog; Src: v-src sarcoma viral oncogene homolog; STAT3 :Signal transducer and activator of transcription 3; TKI: tyrosine kinase inhibitors.