Abstract
Patients with EGFR gene mutation often obtain de novo resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) or develop secondary resistance to EGFR-TKIs after taking EGFR-TKI therapy. Traditional Chinese medicine (TCM) with different treatment principles, in combination with EGFR-TKIs, plays an important role in the treatment of cancers including resistant non-small cell lung cancer (NSCLC). However, inappropriate use of TCM herbs may induce resistance to gefitinib. Therefore, it is of a great value to evaluate which TCM treatment principle should be combined with EGFR-TKIs, and which one should be avoided, and find out the potential mechanisms. The lentiviral transfection assay was used for overexpression of PIK3CA mutation gene in PC-9 cells to construct PC-9-PIK3CA-mutation (PC-9-PIK3CA-M) cells. Cell proliferation, apoptosis, and the expression of EGFR/PI3K/AKT and EGFR/RAS/RAF/ERK in PC-9-PIK3CA-M and H1975 cells treated by the typical cooling-heat drug, Qing-kai-ling (QKL) and Tan-re-qing (TRQ), or the typical warming-yang drug, Shen-fu (SF) and gefitinib treatment, were detected by MTT, Annexin V/PI double labeling, and Western blot assays, respectively. Tumor xenograft and immunohistochemistry experiments were carried out to confirm the in vitro findings. PC-9-PIK3CA-M cells were less sensitive to gefitinib, when compared with PC-9 cells. QKL injection and TRQ injection, not SF injection, combined with gefitinib induced significantly increased cell growth inhibition and apoptosis in PC-9-PIK3CA-M and H1975 cells. SF injection antagonized the effect of gefitinib in promoting cancer cell apoptosis. QKL injection and TRQ injection increased the sensitivity of gefitinib by inhibiting the phosphorylation of AKT or ERK in H1975 and PC-9-PIK3CA-M cells. Similar findings were observed in vivo in H1975 xenograft mouse model. QKL and TRQ, with cooling-heat TCM treatment principle, should be combined with gefitinib in the treatment of NSCLC. Furthermore, warming-yang drug SF should be avoided to be used together with EGFR-TKIs.
Highlights
Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are the preferred treatment for intermediate to advanced stage non-small cell lung cancer (NSCLC) in patients with EGFR gene mutation [1, 2]
A case report by Hwang et al indicated that some Traditional Chinese medicine (TCM) herbs may even induce resistance to gefitinib [6]. is phenomenon is similar to that in the western medicine that certain drugs, such as antifungal drugs, could induce primary and acquired resistance of EGFR-TKI in lung cancer [7]. erefore, it is of a great value to explore which TCM treatment principle should be combined with EGFR-TKIs and which principle should be avoided to be combined with EGFR-TKIs using the TCM theory
We have previously demonstrated that EGFR gene mutated NSCLC patients, who are sensitive to EGFR-TKIs, were more likely with Yin-cold (YC) TCM syndrome type [8]
Summary
Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are the preferred treatment for intermediate to advanced stage non-small cell lung cancer (NSCLC) in patients with EGFR gene mutation [1, 2]. We have previously demonstrated that EGFR gene mutated NSCLC patients, who are sensitive to EGFR-TKIs, were more likely with Yin-cold (YC) TCM syndrome type [8]. We noticed that patients with primary or secondary resistance to EGFR-TKIs have more chance to be diagnosed with YH syndrome type. According to TCM theory, we propose a hypothesis that cooling-heat, rather than warmingyang TCM treatment principle, should be used when combined with EGFR-TKIs and may help to improve the efficacy of EGFR-TKIs in resistant NSCLC
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
