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HER3 as biomarker and therapeutic target in pancreatic cancer: new insights in pertuzumab therapy in preclinical models.

Thomas G, Chardès T, Gaborit N, Mollevi C, Leconet W, Robert B, Radosevic-Robin N, Penault-Llorca F, Gongora C, Colombo PE, Lazrek Y, Bras-Goncalves R, Savina A, Azria D, Bazin H, Pèlegrin A, Larbouret C - Oncotarget (2014)

Bottom Line: We correlated in vitro and in vivo HER3 expression and neuregulin dependency with the inhibitory effect of pertuzumab on cell viability and tumor progression.Finally, HER2 and HER3 were co-expressed in 11% and HER3 alone in 27% of the 45 pancreatic ductal adenocarcinomas analyzed by immunohistochemistry.Further studies in clinical samples are required to confirm these findings and the interest of combining anti-HER2 and anti-HER3 therapeutic antibodies.

View Article: PubMed Central - PubMed

Affiliation: IRCM, Institut de Recherche en Cancérologie de Montpellier, Montpellier, F-34298, France; INSERM, Unit 896, Montpellier, F-34298, France; Université Montpellier1, Montpellier, F-34298, France; ICM, Montpellier, France. Institut Roche de Recherche et Médecine Translationnelle, Boulogne Bilancourt, France.

ABSTRACT
The anti-HER2 antibody pertuzumab inhibits HER2 dimerization and affects HER2/HER3 dimer formation and signaling. As HER3 and its ligand neuregulin are implicated in pancreatic tumorigenesis, we investigated whether HER3 expression could be a predictive biomarker of pertuzumab efficacy in HER2low-expressing pancreatic cancer. We correlated in vitro and in vivo HER3 expression and neuregulin dependency with the inhibitory effect of pertuzumab on cell viability and tumor progression. HER3 knockdown in BxPC-3 cells led to resistance to pertuzumab therapy. Pertuzumab treatment of HER3-expressing pancreatic cancer cells increased HER3 at the cell membrane, whereas the anti-HER3 monoclonal antibody 9F7-F11 down-regulated it. Both antibodies blocked HER3 and AKT phosphorylation and inhibited HER2/HER3 heterodimerization but affected differently HER2 and HER3 homodimers. The pertuzumab/9F7-F11 combination enhanced tumor inhibition and the median survival time in mice xenografted with HER3-expressing pancreatic cancer cells. Finally, HER2 and HER3 were co-expressed in 11% and HER3 alone in 27% of the 45 pancreatic ductal adenocarcinomas analyzed by immunohistochemistry. HER3 is essential for pertuzumab efficacy in HER2low-expressing pancreatic cancer and HER3 expression might be a predictive biomarker of pertuzumab efficacy in such cancers. Further studies in clinical samples are required to confirm these findings and the interest of combining anti-HER2 and anti-HER3 therapeutic antibodies.

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HER2 and HER3 expression was assessed by IHC in 42 pancreatic cancer samplesA, HER2-negative case, B, HER3-negative case, C, HER2-positive case and D, HER3-positive case.
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Figure 6: HER2 and HER3 expression was assessed by IHC in 42 pancreatic cancer samplesA, HER2-negative case, B, HER3-negative case, C, HER2-positive case and D, HER3-positive case.

Mentions: Finally, we investigated whether HER2 and HER3 are co-expressed in PDAC specimens from 45 patients by immunohistochemistry (IHC). HER2 was detected by IHC in 10/45 PDAC specimens (22%). HER2 expression was moderate in two of them and weak in the others (Figure 6). HER3 was detected in 12/44 PDAC (27%). In all cases, staining was weak but clearly positive. HER2/HER3 co-expression was observed in 5/44 PDAC (11%); specifically, 42% of the HER3-positive PDAC samples were also HER2-positive. HER2 and HER3 were mainly detected in the cytoplasm (Figure 6C and) and weak membrane expression was observed in several specimens.


HER3 as biomarker and therapeutic target in pancreatic cancer: new insights in pertuzumab therapy in preclinical models.

Thomas G, Chardès T, Gaborit N, Mollevi C, Leconet W, Robert B, Radosevic-Robin N, Penault-Llorca F, Gongora C, Colombo PE, Lazrek Y, Bras-Goncalves R, Savina A, Azria D, Bazin H, Pèlegrin A, Larbouret C - Oncotarget (2014)

HER2 and HER3 expression was assessed by IHC in 42 pancreatic cancer samplesA, HER2-negative case, B, HER3-negative case, C, HER2-positive case and D, HER3-positive case.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4196190&req=5

Figure 6: HER2 and HER3 expression was assessed by IHC in 42 pancreatic cancer samplesA, HER2-negative case, B, HER3-negative case, C, HER2-positive case and D, HER3-positive case.
Mentions: Finally, we investigated whether HER2 and HER3 are co-expressed in PDAC specimens from 45 patients by immunohistochemistry (IHC). HER2 was detected by IHC in 10/45 PDAC specimens (22%). HER2 expression was moderate in two of them and weak in the others (Figure 6). HER3 was detected in 12/44 PDAC (27%). In all cases, staining was weak but clearly positive. HER2/HER3 co-expression was observed in 5/44 PDAC (11%); specifically, 42% of the HER3-positive PDAC samples were also HER2-positive. HER2 and HER3 were mainly detected in the cytoplasm (Figure 6C and) and weak membrane expression was observed in several specimens.

Bottom Line: We correlated in vitro and in vivo HER3 expression and neuregulin dependency with the inhibitory effect of pertuzumab on cell viability and tumor progression.Finally, HER2 and HER3 were co-expressed in 11% and HER3 alone in 27% of the 45 pancreatic ductal adenocarcinomas analyzed by immunohistochemistry.Further studies in clinical samples are required to confirm these findings and the interest of combining anti-HER2 and anti-HER3 therapeutic antibodies.

View Article: PubMed Central - PubMed

Affiliation: IRCM, Institut de Recherche en Cancérologie de Montpellier, Montpellier, F-34298, France; INSERM, Unit 896, Montpellier, F-34298, France; Université Montpellier1, Montpellier, F-34298, France; ICM, Montpellier, France. Institut Roche de Recherche et Médecine Translationnelle, Boulogne Bilancourt, France.

ABSTRACT
The anti-HER2 antibody pertuzumab inhibits HER2 dimerization and affects HER2/HER3 dimer formation and signaling. As HER3 and its ligand neuregulin are implicated in pancreatic tumorigenesis, we investigated whether HER3 expression could be a predictive biomarker of pertuzumab efficacy in HER2low-expressing pancreatic cancer. We correlated in vitro and in vivo HER3 expression and neuregulin dependency with the inhibitory effect of pertuzumab on cell viability and tumor progression. HER3 knockdown in BxPC-3 cells led to resistance to pertuzumab therapy. Pertuzumab treatment of HER3-expressing pancreatic cancer cells increased HER3 at the cell membrane, whereas the anti-HER3 monoclonal antibody 9F7-F11 down-regulated it. Both antibodies blocked HER3 and AKT phosphorylation and inhibited HER2/HER3 heterodimerization but affected differently HER2 and HER3 homodimers. The pertuzumab/9F7-F11 combination enhanced tumor inhibition and the median survival time in mice xenografted with HER3-expressing pancreatic cancer cells. Finally, HER2 and HER3 were co-expressed in 11% and HER3 alone in 27% of the 45 pancreatic ductal adenocarcinomas analyzed by immunohistochemistry. HER3 is essential for pertuzumab efficacy in HER2low-expressing pancreatic cancer and HER3 expression might be a predictive biomarker of pertuzumab efficacy in such cancers. Further studies in clinical samples are required to confirm these findings and the interest of combining anti-HER2 and anti-HER3 therapeutic antibodies.

Show MeSH
Related in: MedlinePlus