This could be due to the involvement of compensatory mechanisms as reported 
for STAT 3 in response to dasatinib in head and neck cancer and mesothelioma.
The reality that everyday administration of EBIP prospects to a considerable reduction in the growth of SCID mice xenografts of breast cancer MDA MB 468 cells, that express quite substantial levels of EGFR and minor or no other ErbBs, more corroborates our postulation that EBIP could be utilized to inhibit development of EGFR expressing tumors.
This and the truth that EBIP also inhibits growth of numerous other breast cancer cells that express other members of the EGFR household PD-183805 and also inhibits heregulininduced activation of HER 2 and HER 3 in breast cancer cells propose that EBIP, as has been reported for ERRP could potentially be a pan ErbB inhibitor. Even though the exact mechanisms by which EBIP inhibits activation of EGFR and its family members and in turn cellular growth are not entirely understood, earlier studies with ERRP suggests that this peptide, which is structurally and functionally equivalent to EBIP, inhibits EGFRs function by sequestering EGFRs ligand leading to heterodimerization with a single of the EGFR household members, which is functionally inactive.
We think that the related phenomenon is responsible for the development inhibitory properties of EBIP, given that EBIP contains the ligand binding domain of EGFR. The chance that ectodomains of EGFR inhibit EGFRs signaling by sequestering their ligands comes from the observation by Garrett et al that a truncated EGFR with only 3 of the 4 extracellular Evodiamine subdomains binds EGF and TGF with at least ten fold higher affinity than the full length extracellular domain of EGFR rendering them unavailable for binding to and activation of receptors. Given that EBIP, like ERRP, lacks most of the extracellular domain IV, it is sensible to predict that EBIP will also be effective in preferentially binding/sequestering ligands of EGFR.
Our current data help this contention in that EBIP co immunoprecipitated with EGFR following induction with TGF. In addition to EGFRs, aberrant activation of c Src has been observed in a lot of solid tumors like Pelitinib breast cancers. Moreover, co overexpression of EGFRs and c Src has been proven to be related with increased incidence of metastasis and poor survival. Due to the fact of Srcs involvement in the advancement and progression of a lot of reliable tumors, numerous Src inhibitors such as dasatinib, have been examined in solid tumors, but with minimal achievement. This could partly be due to the presence and dominance of compensatory pathways in the cancer cells. For instance, STAT 3 pathway is inhibited by dasatinib transiently and by means of a compensatory pathway, and is re activated as early as 24h.
It has been proposed that STAT 3 inhibitors present synergistic interactions with dasatinib in HNSCC. Consequently, in order to achieve a far better therapeutic efficacy, targeting several pathways simultaneously is warranted. Our observation that dasatinib collectively with EBIP brings about greater inhibition of development of breast cancer cells in vitro and in vivo supports our postulation that simultaneous targeting of a number of signaling pathways is an effective therapeutic strategy. We do feel this is very first of a sort study that demonstrates the usefulness of a mixture treatment of EGFR and Src inhibitors in breast cancer.
for STAT 3 in response to dasatinib in head and neck cancer and mesothelioma.The reality that everyday administration of EBIP prospects to a considerable reduction in the growth of SCID mice xenografts of breast cancer MDA MB 468 cells, that express quite substantial levels of EGFR and minor or no other ErbBs, more corroborates our postulation that EBIP could be utilized to inhibit development of EGFR expressing tumors.
This and the truth that EBIP also inhibits growth of numerous other breast cancer cells that express other members of the EGFR household PD-183805 and also inhibits heregulininduced activation of HER 2 and HER 3 in breast cancer cells propose that EBIP, as has been reported for ERRP could potentially be a pan ErbB inhibitor. Even though the exact mechanisms by which EBIP inhibits activation of EGFR and its family members and in turn cellular growth are not entirely understood, earlier studies with ERRP suggests that this peptide, which is structurally and functionally equivalent to EBIP, inhibits EGFRs function by sequestering EGFRs ligand leading to heterodimerization with a single of the EGFR household members, which is functionally inactive.
We think that the related phenomenon is responsible for the development inhibitory properties of EBIP, given that EBIP contains the ligand binding domain of EGFR. The chance that ectodomains of EGFR inhibit EGFRs signaling by sequestering their ligands comes from the observation by Garrett et al that a truncated EGFR with only 3 of the 4 extracellular Evodiamine subdomains binds EGF and TGF with at least ten fold higher affinity than the full length extracellular domain of EGFR rendering them unavailable for binding to and activation of receptors. Given that EBIP, like ERRP, lacks most of the extracellular domain IV, it is sensible to predict that EBIP will also be effective in preferentially binding/sequestering ligands of EGFR.
Our current data help this contention in that EBIP co immunoprecipitated with EGFR following induction with TGF. In addition to EGFRs, aberrant activation of c Src has been observed in a lot of solid tumors like Pelitinib breast cancers. Moreover, co overexpression of EGFRs and c Src has been proven to be related with increased incidence of metastasis and poor survival. Due to the fact of Srcs involvement in the advancement and progression of a lot of reliable tumors, numerous Src inhibitors such as dasatinib, have been examined in solid tumors, but with minimal achievement. This could partly be due to the presence and dominance of compensatory pathways in the cancer cells. For instance, STAT 3 pathway is inhibited by dasatinib transiently and by means of a compensatory pathway, and is re activated as early as 24h.
It has been proposed that STAT 3 inhibitors present synergistic interactions with dasatinib in HNSCC. Consequently, in order to achieve a far better therapeutic efficacy, targeting several pathways simultaneously is warranted. Our observation that dasatinib collectively with EBIP brings about greater inhibition of development of breast cancer cells in vitro and in vivo supports our postulation that simultaneous targeting of a number of signaling pathways is an effective therapeutic strategy. We do feel this is very first of a sort study that demonstrates the usefulness of a mixture treatment of EGFR and Src inhibitors in breast cancer.
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