data claim that squamous cell carcinoma may be more painful and sensitive to IGF 1R TKIs than lung adenocarcinoma is. But, our present results and previous reports show that tumor histology is not a predictive marker of reaction to IGF 1R targeted approaches. We also observed significantly pifithrin alpha increased pIGF 1R/IR levels in patients with a history of TS, those with mut K Ras, and those with wt EGFR, that have been strongly associated with poor response to EGFR TKIs. Numerous studies have suggested that human cancer cells can be very dependent on single or multiple pathways that are overly activated, conferring tumorigenic potential,29 31 and effective anticancer therapeutic strategies would rely on the selection of patients harboring tumors that rely on these pathways for cell growth and survival. Our previous and current Messenger RNA studies show that transformed lung epithelial cell lines induced by TS components had an elevated expression of pIGF 1R/IR and were sensitive for the molecularly specific techniques against the IGF 1R system. 32 33 TS elements including NNK have been shown to induce genetic improvements in p53 and PTEN, which control IGF 1R appearance and IGF 2. 34 35 NNK also can induce phosphorylation and degradation of p53 and inactivation of PTEN via activation of Akt. Impact of the IGF 1R pathway in cell proliferation and survival suggested that targeting IGF 1R could possibly be an effective therapeutic technique for NSCLC patients with TS history, 40 Even though we did not have mechanistic evidence for TS induced activation of IGF 1R/IR signaling in lung carcinogenesis. This concept and our subsequent findings, such as the features of patients with NSCLC harboring elevated pIGF 1R/IR levels were negatively correlated with those of patients harboring EGFR mutation, and PQIP therapy successfully inhibited ubiquitin conjugating stimulation of the IGF 1R pathway but had little anti-tumor activity in mut EGFR indicating NSCLC cells, led us to hypothesize that the record of TS and EGFR mutation are predictive biomarkers for no responsiveness to IGF 1R TKIs. However, we found that only a part of human NSCLC cell lines with large pIGF 1R/IR degrees and wt EGFR were painful and sensitive to PQIP therapy. These observations suggest that EGFR mutation is not a predictive marker to a reaction to IGF 1R TKI based treatments. Thinking about the potential mechanisms of cross-talk between EGFR and IGF 1R signaling,19, 36-38 inhibition of IGF 1R signaling has been compensated for by enhanced activation through EGFR. Nevertheless, NSCLC cells indicating mut Ras did not show significantly enhanced sensitivity in response to company targeting of IGF 1R and EGFR by treatment with PQIP and the EGFR TKI erlotinib, while the same program significantly decreased cell viability in a subset of head and neck squamous cell carcinoma cell lines carrying wt Ras.