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There has been a lot of interest lately in the PI3K and MEK pathways as well as RAS inhibition, so it was it particularly apt to spot a recent paper in Cancer Research yesterday and get an e-copy from the first named author (Sue Mee) within a few hours of the request. I was delighted, as sometimes you wonder if your request goes into a black hole, only to fall out months later or worse, not at all.
It is now clear that RAS is one of the most deregulated pathways in cancer and may have major implications in the development of resistance, as witnessed by activated mutations in BRAF and PIK3CA. The loss of PTEN function recently observed in common carcinomas such as colon and lung cancers, together with KRAS mutations may also be related. There is a suspicion that the PI3K pathway activation strongly influences the sensitivity of RAS mutant cells to MEK inhibitors. Activating mutations in PIK3CA reduce the sensitivity to MEK inhibition, whereas PTEN mutations seem to cause complete resistance.
What was interesting about the Mee et al., article is that they show that:
"… down-regulation of PIK3CA resensitizes cells with co-occurring KRAS and PIK3CA mutations to MEK inhibition. At the molecular level, the dual inhibition of both pathways seems to be required for complete inhibition of the downstream mammalian target of rapamycin effector pathway and results in the induction of cell death.
Finally, we show that whereas inactivation of either the MEK or PI3K pathway leads to partial tumor growth inhibition, targeted inhibition of both pathways is required to achieve tumor stasis."
It thus looks from this research that inhibition of both MEK and PI3-kinase will be needed to avoid KRAS and BRAF mutations downstream and that inatcivation of either MEK or PI3K alone leads to partial but not complete tumour inhibition.
If I were a Pharma company with both a MEK and a PI3K inhibitor, I would be jumping for joy at this news because it certainly provides the clearest and most compelling rationale yet for testing in the clinic of inhibitors of both pathways together.
PI3 Kinase inhibitors are now being tested in the clinic by numerous companies with many others in preclinical research. However, who's got a MEK inhibitor?
Off the top of my head I can of think Merck, AstraZeneca, Array, Pfizer, Bayer and others to name a few.
There are a number of biotechnology companies developing numerous kinase inhibitors to target different pathways. The RAS mutation described earlier may also be a potential target and Bayer's sorafenib (Nexavar) has been shown to inhibit RAS as well as VEGF, as shown in the second paper in the references below.
Still, as big Pharma gets smarter, their oncology R&D and licensing groups begin to realise that to compete in the future, they will need to have a broad portfolio of different kinase inhibitors targeting multiple pathways where you can mix and match accordingly. The landscape is changing as we have noticed by the number of new products groups calling us for a broad look at what's happening both now and in the future.
One thing is very clear though. When basic research like this paints a cohesive picture, clinical R&D testing becomes much more focused and less of a crapshoot. That's good news for patients too.
Wee, S., Jagani, Z., Xiang, K., Loo, A., Dorsch, M., Yao, Y., Sellers, W., Lengauer, C., & Stegmeier, F. (2009). PI3K Pathway Activation Mediates Resistance to MEK Inhibitors in KRAS Mutant Cancers Cancer Research, 69 (10), 4286-4293 DOI: 10.1158/0008-5472.CAN-08-4765
Wilhelm SM, Carter C, Tang L, Wilkie D, McNabola A, Rong H, Chen C, Zhang X, Vincent P, McHugh M, Cao Y, Shujath J, Gawlak S, Eveleigh D, Rowley B, Liu L, Adnane L, Lynch M, Auclair D, Taylor I, Gedrich R, Voznesensky A, Riedl B, Post LE, Bollag G, & Trail PA (2004). BAY 43-9006 exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis. Cancer research, 64 (19), 7099-109 PMID: 15466206