Inhibition of functional HER family members increases the sensitivity to docetaxel in human ovarian cancer cell lines.
Human epidermal growth factor (HER) family-targeted therapy combined with standard cytotoxic agents might improve the treatment of ovarian cancer. Human ovarian cancer cell lines OVCAR-3, IGROV-1, and SKOV-3 with differential EGFR, HER2, and HER3 expression levels were used to study whether EGFR-directed (cetuximab) or HER2-directed (trastuzumab, pertuzumab) monoclonal antibodies inhibited cell growth and abrogated activated receptor signaling routes. Possible increase of antiproliferative effects and further activation of caspase-3 as a read-out for apoptosis were analyzed when monoclonal antibodies were combined with docetaxel. Cetuximab alone inhibited cell growth in OVCAR-3 and IGROV-1, which was more pronounced when combined with pertuzumab in OVCAR-3. SKOV-3 cell growth was not significantly affected by any of the antibodies. Cetuximab increased the 50% growth-inhibiting effects of docetaxel in OVCAR-3 and IGROV-1, but not in SKOV-3. Coaddition of pertuzumab to cetuximab plus docetaxel in OVCAR-3 and IGROV-1, and, to a lesser extent trastuzumab in OVCAR-3, inhibited cell growth even further. Caspase-3 activation by docetaxel was enhanced after addition of cetuximab in OVCAR-3 and after addition of cetuximab plus pertuzumab in IGROV-1 and SKOV-3. Functional EGFR-signaling, HER2-signaling, and HER3-signaling routes as shown from abrogation of EGF-stimulated and heregulin-stimulated phosphorylated ERK1/2 by cetuximab, trastuzumab, and pertuzumab, respectively, were shown in OVCAR-3 and IGROV-1, but hardly in SKOV-3. Pertuzumab was able to abrogate phosphorylated HER2 by EGF and heregulin, except in SKOV-3. In conclusion, a combination of docetaxel with inhibitors of HER family members, such as cetuximab plus pertuzumab, may be considered for a clinical trial in ovarian carcinomas with functional receptors.
Department of Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands.
Marcel N A
MN
Bijman
Maria P A
MP
van Berkel
Mirjam
M
Kok
Maarten L
ML
Janmaat
Epie
E
Boven
D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D000077143:Docetaxel; D004357:Drug Synergism; D004789:Enzyme Activation; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D005260:Female; D006801:Humans; D020128:Inhibitory Concentration 50; D010051:Ovarian Neoplasms / Q000378:metabolism / Q000473:pathology*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors; D020893:Receptor, ErbB-3 / Q000037:antagonists & inhibitors; D043823:Taxoids / Q000494:pharmacology*
D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D053148:Caspase 3; D000077143:Docetaxel; D066246:ErbB Receptors; D018719:Erb-b2 Receptor Tyrosine Kinases; D020893:Receptor, ErbB-3; D043823:Taxoids; C512478:EGFR protein, human; C508053:ERBB2 protein, human