Here's an interesting paper that was just published in Cancer Research that describes some factors driving acquired resistance to MET inhibition with small molecules.
MET inhibitors have gained a lot of attention recently (see Comoglio et al's review in the references for a good overview) and we have covered this topic a few times on this blog both in terms of the biology and also on promising inhibitors such as ArQule/DaiichiSankyo's ARQ-197, which is the leading compound in this field.
Acquired resistance is a common and limiting problem for chronic therapy with many tyrosine kinase inhibitors (TKI), not just MET inhibitors. After initial excitement at seeing some responses though, they appear to stop working. The big question is why, and what underlying mechanisms may be at play?
Of course, while the issue may be a universal one, the resistance mechanisms are not and will differ with each class of TKI and potentially even tumour types or combinations.
The MET gene is disregulated in a number of different tumour types and those cells exhibiting MET amplification may offer a suitable target for drug inhibition. Doing so results in impairment of cell growth and apoptosis.
You can read more about the biology of the c-MET pathway here.
Acquired Resistance to MET
In this important research, the authors decided to see if they could define some of the underlying mechanisms of MET resistance:
"To predict mechanisms of acquired resistance, we generated resistant cells by treating MET-addicted cells with increasing concentrations of the MET small-molecule inhibitors PHA-665752 or JNJ38877605."
They found that cells progressively amplified KRAS, which resulted in increased expression and activation of wild-type (wt) KRAS and in activation of the mitogenactivated protein kinase (MAPK) pathway:
"We show that amplification of wt MET and KRAS is found in cells of diverse histotypes, resistant to different inhibitors.
Moreover, unexpectedly, we observed that resistance to treatment was reversible and that the alterations leading to resistance were lost after drug withdrawal."
This is a very important finding because it may well be helpful for designing future clinical studies, either in combination or in sequence, to reduce the potential for resistance emerging with MET inhibitors, thereby improving the potential for better long term outcomes with treatment.
"Our results suggest that MET and KRAS amplification is a general mechanism of resistance to specific MET inhibitors given that similar results were observed with two small inhibitors and in different cell lines of different histotypes."
My favourite part of this story was not just the identification of potential mechanisms of MET resistance, but some hints of how the learnings from the data could be applied:
"Because specific anti-RAS drugs are not available, we tested the ability of compounds acting downstream RAS (such as U0126, PD325901, and sorafenib) to impair cell viability. We observed that cells resistant to MET inhibitors that underwent KRAS amplification are indeed sensitive to these drugs."
Clearly, our ability to not only predict potential mechanisms of resistance, but also devise strategies for overcoming or preventing it, is crucial for improved clinical development with these agents as well as providing a clear rationale for other inhibitors still in research.
Where there's a viable target, there's a way forward.
Cepero, V., Sierra, J., Corso, S., Ghiso, E., Casorzo, L., Perera, T., Comoglio, P., & Giordano, S. (2010). MET and KRAS Gene Amplification Mediates Acquired Resistance to MET Tyrosine Kinase Inhibitors Cancer Research DOI: 10.1158/0008-5472.CAN-10-0436
Comoglio, P., Giordano, S., & Trusolino, L. (2008). Drug development of MET inhibitors: targeting oncogene addiction and expedience Nature Reviews Drug Discovery, 7 (6), 504-516 DOI: 10.1038/nrd2530