the tumorbearing rats eventually adapted to chronic Smo inhibition and became resistant to the treatment, ergo increasing the importance in identifying potential resistant elements. Hh signaling can also be implicated as an important mediator of cancer stem cell phenotype in pancreas cancer. A few groups have reported to the c-Met kinase inhibitor cellular markers of CSCs in pancreas cancer and the CSCs might be identified by the company appearance of CS133/CXCR4, or CD44/CD24/ ESA. Extractions enriched in cancer cells expressing these markers is remarkably tumorigenic in in vitro and in vivo studies and re capitulate the traits of parent cancers. Investigation of the CSCs discovered increased activation of Hh signaling and other self-renewal signaling pathways. Mueller et al reported anti CSC consequences when pancreas cancers were treated using a mixture of cyclopamine or CUR199691, rapamycin and Posttranslational modification gemcitabine, and treated tumorbearing mice survived longer than control. This is associated with elimination of CD133 showing CSCs. Therefore, approaches targeting CSC signaling pathways are worth discovering technically. GDC 0449, XL139, and LDE225 are oral agents with anti Smo actions in low nanomolar range, and skin Gli 2 expression has been used a possible pharmacodynamic markers for this class of agents. Known negative effects of Hh inhibitors contain muscle spasms, nausea, dysguesia, rhabdomyolysis, and alteration in cholesterol biosynthesis. GDC 0449 is furthest in development and clinical trials assessing the efficacy in combination with gemcitabine and nabpaclitaxel or gemcitabine with and without erlotinib in previously untreated advanced pancreas cancer patients are starting soon. The clinical eff icacy of Smo inhibitors in pancreas cancer remains unclear in the individual agent phase I studies performed up to now. The ability of Hh inhibitors to lower stromal tissue and enhances the delivery of cytotoxic drugs in preclinical studies may be exploited to improve the response rate in pancreas cancer patients. Such therapy gets the potential of benefiting patients with locally advanced level or border-line resectable infection. Possible mechanism of resistance to Smo inhibitors can be learnt from medulloblastoma models, which has been connected to alteration in the binding site of Smo by GDC 0449. For LDE225, weight might be related to a number of factors including Gli2 chromosomal amplification, upreg u l at ion of compensatory trails including PI3K/AKT/mTOR, IGF, and EGFR and, more seldom, point mutations in Smo that generated reactivated Hh signaling and restored cyst development. The weight may be reversed by co therapy with agents targeting the PI3K/AKT/mTOR, IGF axis, or EGFR pathways. PI3K/AKT/mTOR pathway The phosphoinositide 3 kinase /Akt/mammalian target of rapamycin pathway functions as a sensor for vitamins and growth factors, and integrates signals from multiple receptor kinases to regulate kcalorie burning and cellular growth.