DHFR inhibitors, such as the “classical” antifolates methotrexate (MTX) and pemetrexed (MTA, approved by the FDA in 2008 for the treatment of non-squamous NSCLC patients) have been effective in treating many cancer types [26,27,28], their use is diminished as an effect of the high toxicity, the impaired cellular uptake and other resistance-associated mechanisms [29]. The gene discussed is DHFR; the disease is non-small cell lung carcinoma.