Role of Cyclins in ER positive Breast cancers resistance

Now it is increasingly apparent that cyclins may have an increased presumptive role in the resistance to Aromatase inhibitors and hormone driven therapy for ER positive breast cancer. Yes as you apply pressure on the cancer cell by Blocking Receptor ultimately the cell will desensitize  itself from this deadly lack of stimulation. Cancer cells want to survive, Increasing evidences suggest that cell desensitization is by way of   the cytokines.  It is not by mistake that disruption of epigenetic events by Entinostat which ultimately change significantly the profile of cyclins produced by the cell will lead to breaking of cancerous cell resistance to Hormone receptor  driven target therapy.   The cancerous cell uses the NF-kB and c-jun (stress related PI3K/AKT/MTOR) for survival and we know what happens when these pathways reach the epigenetic zone, new cyclins are metabolized to induce resistance.  The proof is in the pudding, only MTOR inhibitors, and anti-CDK break the resistance to AI or SERMs.
Which Cytokines affects induce desensitization is a hot question, and the mechanism trggering the need for desensitization need to be aggressively pursued.  Assumption is that dying cells may through the Wnt and Notch give information that eventually leads to resistance in surviving cells.  How ? when?  remember cell since they are born have the instinctive reflex to survive.  It is their mission, it is their commitment!  Dying cancer cells will have to tell somehow the living cells how and why they are dying for those uninvolved to be prepared and possibly a global cellular desensitization of growth inducing receptor is a reflex.  Indeed it has been shown that cancer cells significantly reduce dependency on growth factor stimulation for an internal "stress" like metabolism.  What trigger this alternative "mode de vie" is in itself a pathway to global resistance to outside stimulation and death inducing external compounds!
On epigenetic level, a switch in transcription, would be enough to alter the cytokines with a resulting resistant change in effects at the receptors!
Here at the CRBCM, work is increasing daily as leads multiply.

The main question is should we incrementally add these agents in a sequential way, or should we give these agents together or all 3 for greater good.   will concurrent use actually disrupt the effect of the other, in other words, should we wait for the resistance to develop in order to add the other mode of of targeting agents when the cancer is counting on it the most?  Adding the MTOR after Avastin failure has proven to be supportive of the sequential  intervention by some reports whereas giving them concurrently may not be additive!  Why? by now receptor site of Avastin is "desensitize" while the surviving cell use the PI3K/MTOR to survive, hit it now with MTOR inhibitor, and Histone deacetylator inhibitor like we are doing now with ER positive breast cancers!