Opposition to growth inhibition by combined EGFR HER2 inhibition correlates with the power of the inhibitors to reduce Akt phosphorylation LNCaP Ubiquitin conjugation inhibitor AI cells expressed higher degrees of Akt phosphorylation in comparison to parental LNCaP cells. Therapy with the combination of erlotinib and trastuzumab, but not the person drugs, dramatically inhibited heregulin 1B induced Akt phosphorylation in LNCaP cells, but not in LNCaP AI. Similarly, the exact same combination inhibited Akt phosphorylation in parental pRNS cells which lack a functional AR, whereas in cells that communicate AR, the drug combination failed to inhibit Akt activity. These results correlate Akt phosphorylation with the growth inhibitory effects of the combination of trastuzumab and erlotinib. Moreover, the AG879 and tyrphostins pyridine AG1478, in combination, inhibited Akt phosphorylation in CSS, although not in FBScontaining medium. While they had little if any impact on cell growth in FBS containing medium, much like trastuzumab and erlotinib, the mix of AG879 and AG1478, although not the patient medications, suppressed growth of pRNS 1 1 cells in CSS containing medium. On another hand, LNCaP AI cells were not development arrested by the latter combination. These results suggest that reduction of cell growth from the drug combination correlates with inhibition of Akt phosphorylation. Reduction of Akt phosphorylation sensitizes castration resistant prostate cancer cells to dual EGFR/HER2 inhibition Finally, we investigated ways of overcoming the resistance of PCa cells to ErbB inhibitors. Because LNCaP AI are not sensitive and painful to combined inhibition of HER2 and EGFR, and expressed higher ErbB3 compared to LNCaP, we investigated whether the increase in ErbB3 contributed to this resistance. Like the aftereffects of a combination of trastuzumab and erlotinib, the combination of AG879 and AG1478 impeded the increase in cell numbers but did Hedgehog pathway inhibitor not reduce them below initial levels in LNCaP cells cultured in FBS, indicating growth arrest but not cell death. However, if the same cells were cultured in CSS, there was a 50% decrease in cell numbers indicating cell death. On another hand, tradition in CSS failed to have a similar effect in LNCaP cells overexpressing ErbB3, suggesting that ErbB3 increase induced resistance to this drug combination. To get a task for Akt phosphorylation in this process, LNCaP cells cultured in CSS experienced improving Akt phosphorylation over a period of 5 days when exposed to vehicle alone whereas once they were exposed to the combination of AG1478 and AG879, Akt phosphorylation was somewhat impeded. On another hand, in LNCaP AI cells resistant for this drug mix, the increase in Akt phosphorylation in a reaction to CSS exposure wasn’t affected. The very fact that Akt phosphorylation improved upon CSS treatment in LNCaP AI cells whereas ErbB3 levels did not shows that other facets also give rise to Akt phosphorylaiton in CRPC.