In Cancer target therapy, BIG IS NOT NECESSARILY BETTER.

Scientists have long understood that our fascination with major pathways in the cell should be modulated
and attention to smaller and intermediary molecules should be heightened.   It is true that driver molecules could be sitting in the main high way of the pathways.  But increasingly, it has become evident that supportive genes that maintain the Pathway flow, those that regulate, modulate, start or maintain the pathways or redirect  differentiation  are just as important and may be at time larger in importance for therapeutic intervention.

The discovery that some major chemotherapy drugs keep some special places in our armamentarium of therapeutic interventions not because of their recognized main effects on genes but rather from their Epigenetic effects, how they affect de-acethylation or methylation, miRNA or other related events, have shown the importance of "secondary" changes they impose!

In Pancreatic cancers, the most recognized Mutation is that involving KRAS ( and secondarily the EGFR).  However attacks or inhibition of KRAS has not assured remarkable successes. Anti-EGFR have not convincingly improved survival although with some effect.  Today Researcher are starting to look at supportive genes: the switch genes, those that keep autophosphorylation on, The Cbl, the Shc, PYK2,
 FAK (cheloid effect), PKB and Lyn, the Grb2, The COT when it comes to MEK.

We have neglected the role of TGF alpha as a stressor in this disease although it is the inducer of EGFR.
We have chosen to ignore AP-1 when it is the major inducer of IL-1 (IL-8) and contributor somehow of exacerbation or a consequence of NF-kB intervention in this disease.

Other aspect is the role of maintenance therapy in metastatic Pancreatic cancers, Indeed we know that Activity at KRAS are somewhat obligatory to the driving of this disease, yet we have not checked the status of the KRAS after completion of primary therapy, and attempted to suppress this this in maintenance setting.

The CRBCM is looking into this also!

(Of note major Mutations still involve  P16ink4A, EGFR, DPC4/SMAD4,BRCA2,MHL1,MSH2,KRAS,CDKN2A,PMS1, and TGF(s)) in pancreatic cancers!