Trastuzumab has been shown to decrease p95 HER2 expression within the painful and sensitive BT474 product and as a putative mechanism of Trastuzumab activity this has been adduced. These include reduced PTEN function, activation of other receptor tyrosine kinases, or mutational activation of PI3K. Another potential mechanism of resistance, discussed in this paper, is the expression of types of HER2 which are functionally pifithrin lively, but lack the Trastuzumab epitope. Such tumors would be expected to stay HER2 dependent for activation of PI3K/AKT signaling but would be resistant to inhibition of the pathway by Trastuzumab. The recent finding that the HER2 kinase inhibitor Lapatinib has antitumor activity in a substantial proportion of Trastuzumab resistant, HER2 overexpressing breast cancer patients suggests that many of these tumors indeed retain a reliance on HER2. p95 HER2 keeps tyrosine kinase activity and has been proven to activate ERK and AKT signaling, but lacks the Trastuzumab binding site. Its expression in human cancers has been correlated with Trastuzumab resistance. Such tumors will be expected to answer methods that inhibit p95 HER2 function or reduce its expression, if this connection is causal. HER2 is definitely an HSP90 dependent Plastid protein that’s degraded and ubiquitinated inside the proteosome in a reaction to HSP90 inhibitors. We show that p95 HER2 maintains its dependence on HSP90. It’s within the cell in a HSP90 complex and is rapidly and potently changed in cells exposed to the HSP90 inhibitor SNX 2112. This does occur at similar levels of chemical required for degradation of full length HER2. This is appropriate for work demonstrating that HSP90 binds to an area within the catalytic domain of HER2. HSP90 inhibitors rapidly weaken HER2 and prevent PI3K/ AKT Icotinib and ERK signaling in tumefaction models with HER2 over-expression, whether or not they express high degrees of endogenous or transfected p95 HER2, Figure 3 Figure 5). More over, we find that HSP90 inhibition potently induces degradation of HER2 and p95 HER2 in vivo and triggers prolonged inhibition of AKT signaling in murine tumor models, at doses that are not hazardous to the host. These data suggest that HSP90 inhibition will soon be of good use in Trastuzumab resistant tumors that retain HER2 reliability, especially those by which resistance is due to p95 HER2 term. We’ve previously demonstrated in tissue culture types that cells transfected with p95 HER2 don’t react to Trastuzumab treatment but are sensitized to the effects of the HER2 kinase inhibitor Lapatinib. Within this report we demonstrate that the F2 1282 Trastuzumab resistant xenograft type expresses high levels of p95 HER2. Within this model, Trastuzumab treatment seems to further boost p95 HER2, probably adding to resistance.