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rom 4 individuals, representing a mutation price of 2. 7%. Apart from PI3K activation through mutation, loss of PTEN represents one more mechanism through which the PI3K AKT pathway can come to be activated. Hence, we also investigated the expres sion status of PTEN in GC. A total of 61 qualified tumor samples in the identical cohort of Chinese GC were exam ined by IHC staining employing an anti T0901317  PTEN antibody. As shown in Table 2 and Figure 1, the loss of PTEN protein expression was identified in 23% in the tested sam ples, constant using the reported price of 20%. Further sequencing evaluation in the 61 samples indicated that PTEN loss overlapped with Braf mutation in 1 case, but was mutually exclusive with PI3KCA and Kras mutations.
Anti tumor efficacy of AZD5363 in gastric PDGCX mouse models with T0901317  PI3KCA mutation or PTEN loss The lack of GC individuals with each PI3KCA mutations and PTEN loss along with the high prevalence of PTEN loss observed in GC triggered us to investigate the response of GC with PTEN loss to AZD5363. Nevertheless, because of the lack of GC cell lines with PTEN loss and wild sort PI3K, we screened 15 gastric PDGCX mouse models established from surgical samples of Chinese GC pa tients. The expression levels of PTEN protein were mea sured by IHC staining and genomic PTEN aberrations were detected by MLPA evaluation respectively. PI3KCA hotspot mutations were screened by direct sequencing. As indicated in Table 4, SGC020, a PDGCX model with a PTEN exon 2 six gene deletion and undetectable PTEN protein expression and SGC100, a PDGCX model har boring a PI3KCA H1047R activating mutation and posi tive PTEN staining, were each identified for AZD5363 anti tumor efficacy study.
As shown in Figure 2A, larger levels of basal phosphor AKT and phosphor S6 were detected by Western blot in SGC100 and SGC020 tumors in comparison to that within the SGC001 PDGCX GANT61 tu mors with PI3K and PTEN wild sort status, indicating the up regulation of AKT signal pathway in SGC100 and SGC020 models. Subsequent we tested the response of SGC100 and SGC020 models to AZD5363. As shown in Figure 2B and 2C, AZD5363 single agent treatment resulted in 60% tumor growth inhibition in SGC100 model but had only marginal effects within the PTEN null SGC020 model. AZD5363 treatment in this study was effectively tolerated and didn't lead to substantial body weight reduction. These information indicate that PI3KCA mutations, but not PTEN loss, predicate the sensitivity to AZD5363 in GC.
Chemotherapy would be the present typical of care for GC. In further work, we preformed in vitro combination of AZD5363 using the commonly applied chemotherapy agents in GC such as Taxotere, SN 38 and Oxaliplatin within a variety of GC cell lines with each PI3KCA muta tion and PTEN loss, PI3KCA mutation alone, and PI3K and PTEN wild sort status. Our information showed that the Digestion combination of AZD5363 with Taxotere, SN 38 and Oxaliplatin resulted in additive or slightly synergistic effect no matter the mutation status in PI3K gene. Previous reports have suggested a function for PTEN loss in chemotherapy resistance. For that reason, we next tested no matter if PTEN loss contributed to Taxotere resist ance, one of the key chemotherapy agents applied clinic ally in GC.
As shown in Figure 2B, Taxotere GANT61 at a human equivalent dose of five mg kg weekly had no effect on tumor growth within the T0901317  SGC020 model with PTEN loss. In contrast, combinations of AZD5363 and Taxotere resulted in substantial tumor inhibition within the PDGCX model, supporting a potential combination tactic for the treatment of GC with PTEN loss. Also, the induction of caspase3 7 by combination of AZD5363 with Taxotere, the hallmark of cell apoptosis, was observed in many tested cell lines, suggesting the anti tumor effect of AZD5363 with Taxotere by induc tion of apoptotic cell death. Pharmacodynamic modulation of AKT signaling by AZD5363 correlates with anti tumor activity To know the mechanism of AZD5363 anti tumor efficacy and its combination with Taxotere in SGC020 and SGC100 models, tumor samples were collected two hours post final dose of AZD5363.
Tissues lysates were subjected to Western blot evaluation of PRAS40 and S6 phosphorylation, each downstream targets of AKT signal ing. As shown in Figure three, AZD5363 single agent treat ment led to up regulated GANT61 pAKT in each SGC100 and SGC020 PDGCX T0901317  models, indicating the engagement of AZD5363 with its certain target. It's noteworthy that the undetectable GANT61 pAKT within the untreated SGC100 and SGC020 tumors was as a consequence of a shorter western blot exposure given that incredibly robust signals were detected within the AZD5363 treated samples. Interestingly, the suppression of AKT downstream signaling monitored by pPRAS40 and pS6 was only observed within the PI3KCA mutant PDGCX model, but not within the PTEN null PDGCX model, correlating with AZD5363 anti tumor efficacy. Constant with our current observa tions in cell cultures, Taxotere treatment led to a moderate enhance of pPRAS40 in SGC20 model along with the addition of AZD5363 blocked this induction. These benefits additional support the