Dual ErbB1 and ErbB2 receptor tyrosine kinase inhibition exerts synergistic effect with conventional chemotherapy in pancreatic cancer

Abstract

Abstract. Patient survival in pancreatic cancer remains poor with gemcitabine (GEM)-based regimens. The target specific molecular agent lapatinib, a dual ErbB1 and ErbB2 receptor tyrosine kinase inhibitor, has shown significant activity against ErbB1 and ErbB2-expressing tumors. Since pancreatic tumors frequently overexpress these proteins, we investigated its effects, both alone and in conjunction with 5-FU or GEM. The pancreatic cancer cell lines PANC-1 and AsPC were treated with varying doses of lapatinib in vitro. The effects on ErbB1/ ErbB2 protein phosphorylation and on the cell survival protein survivin were determined by western blotting. Cytotoxicity was determined by MTT assay and apoptosis was measured using the caspase-3 colorimetric assay. Similar dose-response lapatinib experiments were conducted with varying concentrations of 5-FU or GEM and isobolograms were constructed to evaluate therapeutic synergy. Lapatinib inhibited protein phosphorylation in the range of 4-16 µM, a clinically achievable concentration. The lapatinib-treated cells showed a dose-dependent inhibition of cell proliferation and induction of apoptosis at the same concentrations that blocked ErbB1/ ErbB2 phosphorylation. The addition of 5-FU or GEM to these cells resulted in synergistic effects. The lapatinib-treated cells also demonstrated downregulation of survivin. Simultaneous dual ErbB1 and ErbB2 receptor tyrosine kinase inhibition with lapatinib results in significant reduction of pancreatic cancer cell growth and proliferation. These effects occur at clinically achievable concentrations and are synergistic with the effects of 5-FU or GEM. These findings support the potential role of lapatinib in the treatment of pancreatic cancer.

Proteogenomic Analysis of Pancreatic Cancer Subtypes

“…Among the pathway with gene alterations were the Receptor tyrosine kinase -Ras pathway (altered in 75% of all tumours; Figure S2), Wnt pathway (altered in 29% of all tumours; Figure 5a), the PI3K-mTOR pathway (23%; Figure 5b) and Transforming Growth Factor Beta Signalling Pathway (48%; Figure 5c). These cell signalling pathways have been reported altered in various forms of cancers, including those of the lungs, skin, and breast, were they have also been shown to promote oncogenesis [15,[38][39][40]. Accordingly, we suggest that these signalling pathways may play essential roles in pancreatic cancer and may present inflexion points for targeted therapies aimed at curing pancreatic cancer.…”

Predicting High-Impact Pharmacological Targets by Integrating Transcriptome and Text-Mining Features

“…The top impact target alone, EGFR, mediates 23% of total anti-cancer effect, while the second best target, ERBB2, mediates 22% of total effect. While from purely clinical point of view these numbers seem disproportional, many novel therapies rely on a combinatorial synergy with EGRF and ERBB2 ligands (22)(23). Hence, introduction of novel highimpact targets could alter the survival dynamics even further for at least some of the cancer forms.…”

Emerging Importance of Survivin in Stem Cells and Cancer: the Development of New Cancer Therapeutics

“…Similarly Akt specific SH5, also reduces survivin expression along with the significant reduction in other IAPs in chronic myeloid leukemia (CML), lung and prostate cancer [ 153 , 154 ]. A dual kinase inhibitor, Lapatinib inhibits survivin in pancreatic, breast and ovarian cancers through the down regulation of ErbB1 and ErbB2 phosphorylation or upregulation in BMI1 expression [ 133 , 155 , 156 ]. EGFR inhibitors (Gefitinib, PD153035 and AG1478), MAPK antagonist (PD98059) and PI3K inhibitor (LY294002) have shown their potential to inhibit survivin in breast, lung, pancreatic, colon and ovarian cancer cell lines [ 157 – 160 ].…”