Google: "PMC1221574" for a fascinating (but somewhat poorly written) article about the observed cross talk of two signalling pathways, Androgen Receptor and c-Met in mouse kidneys.
It is first noted that the compound CB 3717 is used to cause genetic damage to mouse kidneys whereupon the ligand for the c-Met signaling ligand: HGF is up-regulated causing a subsequent upregulation of c-Met. It is also noted that testosterone alone upregulates c-Met as well. However, when both compounds: CB 3717 and testosterone are present, there is less up-regulation than with the CB 3717 alone. Likewise, testosterone induced effects are also muted by the presence of CB 3717.
If renal cancer is driven by the Androgen Receptor (note the kidney's proximity to adrenal glands which contain testosterone) and it is blocked by either Enzalutamide or ligand reduction through Abiraterone, c-Met may be up regulated causing tumor cell proliferation. It may also stand to reason that post Cabo, the effects of androgen once again gain potency. In light of this, a simultaneous anti-androgen + cabo regimen make a lot of sense.
What I said last night (before going to bed) doesn't all make sense: Enzalutamide isn't used to treat Kidney cancers (and I would be interested to see them try it for men). I was trying to draw attention to the fact that that this cross talk between AR and c-Met pathways is observed even in kidneys, and that the rationale for combo anti-androgen c-met inhibition trials in prostate cancers (and possibly kidney cancer) makes sense.
I'm a non-specialist trying to understand the leading theories for the driving mechanisms of this cross talk with little success. Google 17283128 and PMC2888393 for papers which seem to present different ways that AR and c-Met are tied together via chemical mechanisms:
17283128: This paper posits that AR disrupts the binding site for SP1 which is important to cause the transcription of c-Met. I take this to mean that the the c-Met receptors themselves aren't synthesized within the cell ribosomes because AR disrupts SP1. So a lot's going on in side the cells.
PMC2888393: This paper posits a relation between the receptor CD44, AR, and c-Met. Namely, CD44v9 signaling (which is closely related to HGF / c-Met) pulls together AR and c-Met into a bundle w/ a whole bunch of other receptors on the cell surface. I take this to mean that once the direct AR pathway is silenced, HGF related pathways take over and creates this bundle of receptors which continues to the signaling needed for cancers to proliferate. So a lot's going on just on the cell membrane.
In light of this vast network, it seems like the more targets hit the better since cell proliferation mechanisms only get more complex as individual paths are blocked off.
"In light of this vast network, it seems like the more targets hit the better since cell proliferation mechanisms only get more complex as individual paths are blocked off."
I understand the logic, but it must be remembered that all these receptors and ligands do more than mediate cancer growth. The more pathways are inhibited, the more negative side effects that are going to occur.
As hbomb once mentioned, it seems odd that in prostate cancer each compound, Abiraterone and (seemingly) Cabo have survival benefit on their own when there seems to be rapid upregulation of the complementary path way not blocked by each. It seems like cells need some amount of time to adjust themselves to actually thriving or proliferating via the pathway halted by the complementary therapy and these two pathways are far from all that's going on. The VEGF-R pathway may be essential to this as Joeflow has noted and seems enjoy to complex cross-talk characteristics with both AR and c-Met path ways.
Sorry to ramble on alone like this: it seems hormone replacement therapy does have a brief effect on RCC. c.f. "Hormonal therapy for metastatic renal cell carcinoma combined androgen and provera followed by high dose tamoxifen."
Note that in kidneys, the effect of hormone replacement therapy is brief; on the other hand, from phase 2 Cabo trials, there seems to be substantial PFS, so it sounds like if there is an AR like driver of RCC (which seems like it would ultimately upregulate c-Met in renal cells anyway), it has less importance than c-Met. The rates of adjustment for cross talk seem very tissue dependent.