I have just finished reading the following article published recently by Yamada, et al.; http://www.ncbi.nlm.nih.gov/pubmed/23045273 and have a couple questions that I hope can be answered. My mother has adenocarcinoma of the lung with EGFR mutation, exon 19 deletion. She initially responded very well to erlotinib for first line tx but has since acquired resistance. We are awaiting results from a second biopsy to hopefully determine the cause of this resistance and choose a clinical trial accordingly. I am assuming that the issue will be T790M as 50% of acquired resistance to EGFR TKIs is due to this mutation. My question is concerning the cell lines used in the article (pc-9, hcc827 and h1975). As I was reading through the article I was assuming that all three of these cell lines had acquired resistance to erlotinib and getfitinib but when I studying figure 3a I realized that only h1975 had the acquired resistance. I flipped to the materials/methods portion to find that cell lines pc-9 and hcc827 both have exon 19 deletions and h1975 has the point mutation L858R and T790M dbl mutation. The article continues to figure 4a which shows wonderful results indicating that the knockout of aki1 is effective in controlling tumor growth in vivo when h1975 cell lines were injected into mice with Aki1 siRNA.
These are my questions:
1.) Is there not a cell line consisting of a double mutation with an exon 19 deletion and T790M?
2.) Would the original mutation matter at all with the efficacy of this potential new therapeutic target? (Does it matter if the original mutation is exon 19 or a point mutation?)
3.) I found this target of interest to be inspiring, but sometimes I'll find articles which bring back areas of research which were already discredited or not as clinically important as it seems. This study was recently published, but has this subject (Aki1 target) been studied ad nauseum or is it actually a new, worthy area of research/study?