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Novel agents that downregulate EGFR, HER2, and HER3 in parallel.

Ferreira RB, Law ME, Jahn SC, Davis BJ, Heldermon CD, Reinhard M, Castellano RK, Law BK - Oncotarget (2015)

Bottom Line: These compounds disrupt disulfide bonds and are termed Disulfide Bond Disrupting Agents (DDAs).DDA RBF3 exhibits anticancer efficacy in vivo at 40 mg/kg without evidence of toxicity.DDAs may complement existing EGFR-, HER2-, and HER3-targeted agents that function through alternate mechanisms of action, and combination regimens with these existing drugs may overcome therapeutic resistance.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry, University of Florida, Gainesville, FL 32611, USA.

ABSTRACT
EGFR, HER2, and HER3 contribute to the initiation and progression of human cancers, and are therapeutic targets for monoclonal antibodies and tyrosine kinase inhibitors. An important source of resistance to these agents arises from functional redundancy among EGFR, HER2, and HER3. EGFR family members contain conserved extracellular structures that are stabilized by disulfide bonds. Compounds that disrupt extracellular disulfide bonds could inactivate EGFR, HER2, and HER3 in unison. Here we describe the identification of compounds that kill breast cancer cells that overexpress EGFR or HER2. Cell death parallels downregulation of EGFR, HER2, and HER3. These compounds disrupt disulfide bonds and are termed Disulfide Bond Disrupting Agents (DDAs). DDA RBF3 exhibits anticancer efficacy in vivo at 40 mg/kg without evidence of toxicity. DDAs may complement existing EGFR-, HER2-, and HER3-targeted agents that function through alternate mechanisms of action, and combination regimens with these existing drugs may overcome therapeutic resistance.

No MeSH data available.


Related in: MedlinePlus

Forced EGFR Expression Sensitizes Cells to EGFR/HER2/HER3-targeted CompoundsA. Vector control or EGFR overexpressing T47D cells were treated with 20 μM NSC624205 or vehicle for 24 hours and photographed. Extensive cell death was observed in the T47D.EGFR cells, but not the T47D.Vector cells. B. Cells treated as in a. were subjected to immunoblot analysis. C. Thymidine incorporation of vector control (T47D.Puro) or EGFR overexpressing (T47D.EGFR) cells treated for 24 hours with increasing concentrations of NSC624203 or LY294002. p values were calculated using Student's unpaired t-test. Results are presented as the average of triplicate determinations ± S.D. Scale bars are 20 μm.
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Figure 3: Forced EGFR Expression Sensitizes Cells to EGFR/HER2/HER3-targeted CompoundsA. Vector control or EGFR overexpressing T47D cells were treated with 20 μM NSC624205 or vehicle for 24 hours and photographed. Extensive cell death was observed in the T47D.EGFR cells, but not the T47D.Vector cells. B. Cells treated as in a. were subjected to immunoblot analysis. C. Thymidine incorporation of vector control (T47D.Puro) or EGFR overexpressing (T47D.EGFR) cells treated for 24 hours with increasing concentrations of NSC624203 or LY294002. p values were calculated using Student's unpaired t-test. Results are presented as the average of triplicate determinations ± S.D. Scale bars are 20 μm.

Mentions: T47D cells are not killed by NSC624205, therefore we examined whether this is because these cells do not overexpress EGFR. Interestingly, T47D cells with enforced EGFR expression underwent cell death in response to NSC624205, but vector control cells did not (Figure 3A). As observed above, NSC624205-mediated cell death correlated with an EGFR electrophoretic mobility shift, and decreased Akt phosphorylation (Figure 3B). Cell proliferation assays showed that similarly, EGFR overexpressing T47D cells were more sensitive to NSC624203 than the control cells (Figure 3C). However, no difference between the two cell lines was observed when proliferation was suppressed using PI3-kinase inhibitor LY294002.


Novel agents that downregulate EGFR, HER2, and HER3 in parallel.

Ferreira RB, Law ME, Jahn SC, Davis BJ, Heldermon CD, Reinhard M, Castellano RK, Law BK - Oncotarget (2015)

Forced EGFR Expression Sensitizes Cells to EGFR/HER2/HER3-targeted CompoundsA. Vector control or EGFR overexpressing T47D cells were treated with 20 μM NSC624205 or vehicle for 24 hours and photographed. Extensive cell death was observed in the T47D.EGFR cells, but not the T47D.Vector cells. B. Cells treated as in a. were subjected to immunoblot analysis. C. Thymidine incorporation of vector control (T47D.Puro) or EGFR overexpressing (T47D.EGFR) cells treated for 24 hours with increasing concentrations of NSC624203 or LY294002. p values were calculated using Student's unpaired t-test. Results are presented as the average of triplicate determinations ± S.D. Scale bars are 20 μm.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4496366&req=5

Figure 3: Forced EGFR Expression Sensitizes Cells to EGFR/HER2/HER3-targeted CompoundsA. Vector control or EGFR overexpressing T47D cells were treated with 20 μM NSC624205 or vehicle for 24 hours and photographed. Extensive cell death was observed in the T47D.EGFR cells, but not the T47D.Vector cells. B. Cells treated as in a. were subjected to immunoblot analysis. C. Thymidine incorporation of vector control (T47D.Puro) or EGFR overexpressing (T47D.EGFR) cells treated for 24 hours with increasing concentrations of NSC624203 or LY294002. p values were calculated using Student's unpaired t-test. Results are presented as the average of triplicate determinations ± S.D. Scale bars are 20 μm.
Mentions: T47D cells are not killed by NSC624205, therefore we examined whether this is because these cells do not overexpress EGFR. Interestingly, T47D cells with enforced EGFR expression underwent cell death in response to NSC624205, but vector control cells did not (Figure 3A). As observed above, NSC624205-mediated cell death correlated with an EGFR electrophoretic mobility shift, and decreased Akt phosphorylation (Figure 3B). Cell proliferation assays showed that similarly, EGFR overexpressing T47D cells were more sensitive to NSC624203 than the control cells (Figure 3C). However, no difference between the two cell lines was observed when proliferation was suppressed using PI3-kinase inhibitor LY294002.

Bottom Line: These compounds disrupt disulfide bonds and are termed Disulfide Bond Disrupting Agents (DDAs).DDA RBF3 exhibits anticancer efficacy in vivo at 40 mg/kg without evidence of toxicity.DDAs may complement existing EGFR-, HER2-, and HER3-targeted agents that function through alternate mechanisms of action, and combination regimens with these existing drugs may overcome therapeutic resistance.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry, University of Florida, Gainesville, FL 32611, USA.

ABSTRACT
EGFR, HER2, and HER3 contribute to the initiation and progression of human cancers, and are therapeutic targets for monoclonal antibodies and tyrosine kinase inhibitors. An important source of resistance to these agents arises from functional redundancy among EGFR, HER2, and HER3. EGFR family members contain conserved extracellular structures that are stabilized by disulfide bonds. Compounds that disrupt extracellular disulfide bonds could inactivate EGFR, HER2, and HER3 in unison. Here we describe the identification of compounds that kill breast cancer cells that overexpress EGFR or HER2. Cell death parallels downregulation of EGFR, HER2, and HER3. These compounds disrupt disulfide bonds and are termed Disulfide Bond Disrupting Agents (DDAs). DDA RBF3 exhibits anticancer efficacy in vivo at 40 mg/kg without evidence of toxicity. DDAs may complement existing EGFR-, HER2-, and HER3-targeted agents that function through alternate mechanisms of action, and combination regimens with these existing drugs may overcome therapeutic resistance.

No MeSH data available.


Related in: MedlinePlus