The epidermal growth factor receptor (EGFR) is a validated therapeutic target in 
non-small cell lung cancer (NSCLC). However, some mutations confer resistance to 
current available agents, especially the frequently occurring T790M mutation. In 
the current study, we have examined, in a NSCLC cell line H1975 containing both 
L858R and T790M mutations, the effect of T790M-specific-siRNAs versus other 
EGFR-specific-siRNAs. T790M-specific-siRNAs were able to inhibit T790M and EGFR 
mRNA, to reduce EGFR protein expression, as well as to reduce the cell growth 
and induce cell caspase activity in H1975 cells. However, this effect showed 
less potency compared to the other EGFR-specific-siRNAs. EGFR-specific-siRNAs 
strongly inhibited cell growth and induced apoptosis in H358, H1650, H292, 
HCC827 and also in H1975 cells, which showed weak response to tyrosine kinase 
inhibitors (TKIs) or cetuximab. The addition of T790M-specific-siRNAs could 
rescue the sensitivity of T790M mutant H1975 cells to TKIs. The combination of 
T790M-specific-siRNAs and cetuximab also additively enhanced cell growth 
inhibition and induction of apoptosis in H1975 cells. Among the anti-EGFR agents 
tested, the strongest biological effect was observed when afatinib was combined 
with T790M-specific-siRNAs. Afatinib also offered extra effect when combined 
with cetuximab in H1975 cells. In conclusion, knock-down of T790M transcript by 
siRNAs further decreases the cell growth of T790M mutant lung cancer cells that 
are treated with TKIs or cetuximab. The combination of a potent, irreversible 
kinase inhibitor such as afatinib, with T790M-specific-siRNAs should be further 
investigated as a new strategy in the treatment of lung cancer containing the 
resistant T790M mutation.