Abnormal expression and signaling of
ErbB receptors has been implicated in multiple epithelial
malignancies, including
pancreatic cancer.
Erlotinib, an
epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), has been recently approved for
pancreatic cancer treatment, but there are no reliable predictors of patient response. Expression of additional
ErbB receptors seems to influence
tumor response to EGFR-targeted
therapy. We analyzed the influence of ErbB3 expression on
pancreatic cancer cell response to
erlotinib treatment. Proliferation assays of five human
pancreatic cancer cell lines were performed following treatment with
erlotinib. Expression and phosphorylation profiles of
ErbB receptors and downstream adaptor
protein (Akt, ERK1/2, STAT3, mTOR) were evaluated following stimulation with
EGF or
neuregulin-beta. The formation of EGFR homodimers and EGFR-ErbB3 heterodimers, necessary to enable ErbB3 downstream signaling, was demonstrated by chemical cross-linking assays. The effects of
RNA inhibition of ErbB3 on sensitivity to
erlotinib treatment were evaluated in AsPC-1
pancreatic cancer cells.
Erlotinib inhibited Akt phosphorylation and proliferation of all the ErbB3-expressing cell lines but did not affect mTOR activation. Cross-linking studies confirmed the presence of EGFR-ErbB3 heterodimers in
pancreatic cancer cells. Only the ErbB3-deficient MIA PaCa-2 cells displayed persistent Akt activation and ongoing proliferation in spite of
erlotinib treatment.
siRNA-mediated inhibition of ErbB3 expression in AsPC-1 cells resulted in acquired resistance to
erlotinib treatment.
Pancreatic cancer cells which lack ErbB3 do not display activation of the ErbB3-PI3K-Akt cascade induced by EGFR/ErbB3 heterodimers and become less critically dependent on EGFR signaling and therefore resistant to
erlotinib.
Pancreatic cancer expression of ErbB3 may be useful for EGFR-targeted
therapy patient selection.