This was a great paper I found while browsing My 6 Sense last night, a free but very cool app on my iPhone that takes my Google Reader rss feeds and intuitively tries to select the individual items (e.g. clinical journal articles on cancer) that are most relevant to me out of hundreds and thousands of items I have stored in there.
Overall, the app does a pretty good job, despite the technical nature of many of the feeds I have in there (mostly cancer journals and science/tech articles), if this one is anything to go by. My only beef is that when sharing or streaming scientific papers with long titles to Twitter, the 140 character limit often truncates the url, leaving some unhappy readers in the lurch as I found out very quickly from the @replies!
Not wishing to disappoint followers, I re-sent the link on Twitter but also thought it would be interesting to review here on Research Blogging as well.
Now, basal-like breast cancers (BLBC) are not very nice, in fact they're highly aggressive and may confer a slightly poorer prognosis as a result, yet few if any current therapies are actually targeted at this particular subtype.
The good news is that BLBC do over-express EGFR, but the bad news is that resistance to current EGFR targeted therapies has been well documented, suggesting that something else is at play that causes the resistance to develop. Finding out what that might be may possibly offer a new therapeutic intervention strategy that could be explored, either in combination or in sequence.
It has also been observed in other studies that Notch signalling and activation is prevalent in BLBC. The authors of this paper therefore decided to see what would happen with combined EGFR and Notch inhibition in animals studies:
"We show that although inhibition of either EGFR or Notch signaling alone is insufficient to suppress basal-like breast tumor cell survival and proliferation, simultaneous inhibition uncovers a synthetic lethal relationship between these two oncogenic pathways. This lethality is due in part to significant decreases in AKT activation caused by combined EGFR and Notch inhibition.
Expression of the activated form of Notch1 restores AKT activity and enables cells to overcome cell death after dual-pathway blockade. Combined pathway inhibition is also dramatically more effective at suppressing tumor growth in mice than blocking EGFR or Notch signaling alone."
In breast cancer it would appear that phosphatidylinositol 3-kinase (PI3K)–AKT signaling is the best characterised mechanism to date of Notch-dependent resistance to cell death. AKT is also a recognized mediator of resistance to EGFR inhibition. Thus a much clearer picture begins to emerge whereby compensatory pathways of resistance also need to be considered in the treatment strategy.
Whether a combination of EGFR, AKT and PI3K inhibitors would work in women with basal like breast cancer isn't yet clear, but based on the preclinical evidence from this and other research, it's probably a strategy worth investigating.
You read it here first 😉
Dong, Y., Li, A., Wang, J., Weber, J., & Michel, L. (2010). Synthetic Lethality through Combined Notch-Epidermal Growth Factor Receptor Pathway Inhibition in Basal-Like Breast Cancer Cancer Research, 70 (13), 5465-5474 DOI: 10.1158/0008-5472.CAN-10-0173