Aki1 therapeutic target for EGFR acquired resistance - 1249652

jbenjamin1
Posts:2

Hi There,

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?

Thanks,

Jess

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Reply # - October 28, 2012, 12:22 PM

catdander
Posts:

Hi Jess, welcome to Grace. I'm very sorry you're needing to do so much in-depth learning on your mom's behalf. I must say you're questions seem to be very logical but I can't help with the answers except to agree that there is much lab science that ends up not panning out in clinical studies. However it is all important to move forward.

I will link you to our library of info on acquired resistance and I will also contact a doctor on your behalf to comment on your questions. You should hear back within 12 hours.

I hope your mother's next treatment is as effective as the first.

Janine
forum moderator

I don't think so but you may need to log off to access these links.

this is from our "Focused Cancer Info" link above then I choose from the archives menu EGFR mutations...
http://cancergrace.org/lung/category/lung-cancer/general-lung-cancer-is…

this is from our forum file,
http://cancergrace.org/forum/cancer-treatments-symptom-management/egfr-…

Reply # - October 28, 2012, 12:40 PM

Dr Pennell
Posts: 139

Wow, this is probably the most technical question I have ever seen on this board. I have to preface my answer by saying that I am not a basic scientist, so the specifics of signaling pathways may be beyond my capacity to answer.

The H1975 cell line is the most commonly used cell line containing both an activating mutation and the T790M resistance mutation. I would hazard a guess that there are cell lines in individual labs generated from patient samples that contain exon 19 deletions and T790M, but I do not know if there are commercially available cell lines with both.

You are correct, the signaling from EGFR downstream to Akt happens in all activating mutations, so inhibition of this pathway would be effective no matter what the actual mutation was (exon 19 or 21).

I also agree with you that I would temper my enthusiasm for this potential mechanism of overcoming resistance, although it does sound intriguing. This does appear to be a new discovery, and I'm certain it will be pursued actively, but this is a very early observation in a cell culture dish and is a long long way from being applied to an actual patient. This type of publication is really not meant for the lay audience, but in the electronic era, with lots of highly educated and motivated patients and family members out there, this type of paper gets picked up and often blown out of proportion to its significance. It might be worth keeping an eye on though!

Reply # - October 29, 2012, 03:56 PM

jbenjamin1
Posts: 2

Thank you very much Dr. Pennell for your quick and thoughtful reply. I can appreciate your comment about motivated patients and family members, but unfortunately staying up-to date with the latest research is a necessity for those of us living in remote areas with second-rate cancer centers. I nfact an oncologist from Dana Farber told us that our local cancer center uses the standard of care from ten years ago. The local oncologists are clueless about personalized treatment and my mother has no out of network coverage. So I am extremely grateful to this site for providing an up-to-date resource for people like us who have to be proactive in researching and requesting non-traditional treatment options.

Thank you again for your expertise.

-Jess

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