PHENOMENA SUGGESTING EVOLUTION OF GENETIC AND METABOLIC PROCESSES!

*It is now suggested that as receptor fail, there is a secondary increase of its specific growth factors which lead to stimulation of other susceptible receptors including MUC gene.  What trigger the neoplastic transformation is fuzzy.  However we know that the quantity of stimulation, the persistence of the stimulation, the stress induced at the failing receptor, stress which induces the NF-kB, c-JUN and eventually c-Fos and c-MYC the gene global amplifier, methylation of genes and reversal of mesenchymal transformation at MEK most likely, with its impact on EGFR.   And through the RAS/MAPK,  which interacts with PTEN, by now repressed!   Neoplastic transformation is bound to happen.  Particularly on a background of genetic Heterogenity, something unpredictable is bound to happen!

*The closeness of VEGF and Hypoxic stress/ phenomena is now legendary!   Hypoxia is disturbing at cellular membrane but principally in the Mitochondria where the respiratory system of the cell is located.
It leads to formation of (Reactive oxygen species) superoxide and oxygen free radicals that need dampen by natural anti-oxidants which by the way include Uric Acid.  Because of lack of these anti-oxidant (Asian "obsession" with veggies, in a subset of Asians, we hypothesize that insufficient anti-Oxidant and certain genetic susceptibility factor, ultimately lead to a number of Mutations including EGFR Mutation.  Effects on other genes including the MUC2 gene will lead to respiratory system failure, in other words, occurrence of lung cancer (Adenocarcinoma) in these women. Sex/Steroid receptors in female patients may be involved in the susceptibility.  The story does not stop here however since the Mitochondria takes the full effect of MTOR, the preserver of survival,  As the process evolve, the MTOR will take the brunt of the changes and therefore will be increasingly important suggesting MTOR are more important after failure of Anti-VEGF!  It is not surprising that combination of the 2 agents failed.  VEGF effect seems to depend on MTOR preservation at some level but once the VEGF is incapacitated (resitant disease) MTOR inhibition is a logical step!