Dasatinib Treatment Increases Sensitivity to c-Met Inhibition in Triple-Negative Breast Cancer Cells.

In pre-clinical studies, triple-negative breast cancer (TNBC) cells have demonstrated sensitivity to the multi-targeted kinase inhibitor dasatinib; however, clinical trials with single-agent dasatinib showed limited efficacy in unselected populations of breast cancer, including TNBC. To study potential mechanisms of resistance to dasatinib in TNBC, we established a cell line model of acquired dasatinib resistance (231-DasB). Following an approximately three-month exposure to incrementally increasing concentrations of dasatinib (200 nM to 500 nM) dasatinib, 231-DasB cells were resistant to the agent with a dasatinib IC50 value greater than 5 µM compared to 0.04 ± 0.001 µM in the parental MDA-MB-231 cells. 231-DasB cells also showed resistance (2.2-fold) to the Src kinase inhibitor PD180970. Treatment of 231-DasB cells with dasatinib did not inhibit phosphorylation of Src kinase. The 231-DasB cells also had significantly increased levels of p-Met compared to the parental MDA-MB-231 cells, as measured by luminex, and resistant cells demonstrated a significant increase in sensitivity to the c-Met inhibitor, CpdA, with an IC50 value of 1.4 ± 0.5 µM compared to an IC50 of 6.8 ± 0.2 µM in the parental MDA-MB-231 cells. Treatment with CpdA decreased p-Met and p-Src in both 231-DasB and MDA-MB-231 cells. Combined treatment with dasatinib and CpdA significantly inhibited the growth of MDA-MB-231 parental cells and prevented the emergence of dasatinib resistance. If these in vitro findings can be extrapolated to human cancer treatment, combined treatment with dasatinib and a c-Met inhibitor may block the development of acquired resistance and improve response rates to dasatinib treatment in TNBC.

EGFR and HER2 inhibition in pancreatic cancer.

The aim of this study was to investigate the effect of lapatinib, a selective inhibitor of EGFR/HER2 tyrosine kinases, on pancreatic cancer cell lines both alone and in combination with chemotherapy. Two cell lines, BxPc-3 and HPAC, displayed the greatest sensitivity to lapatinib (IC(50)<2 µM). Lapatinib also demonstrated some activity in three K-Ras mutated pancreatic cancer cell lines which displayed resistance to erlotinib. Drug effect/combination index (CI) isobologram analysis was used to study the interactions of lapatinib with gemcitabine, cisplatin and 5'deoxy-5'fluorouridine. Concentration-dependent anti-proliferative effects of lapatinib in combination with chemotherapy were observed. To evaluate the potential effect of lapatinib in pancreatic cancer tumours, and to identify a subset of patient most likely to benefit from lapatinib, expression of EGFR and HER2 were investigated in 72 pancreatic cancer tumour specimens by immunohistochemistry. HER2 membrane expression was observed in only 1 % of cases, whereas 44 % of pancreatic tumours expressed EGFR. Based on our in vitro results, lapatinib may provide clinical benefit in EGFR positive pancreatic ductal adenocarcinoma.

Targeted treatment of advanced and metastaticbreast cancer with lapatinib.

Improved molecular understanding of breast cancer in recent years has led to the discovery of important drug targets such as HER-2 and EGFR. Lapatinib is a potent dual inhibitor of HER-2 and EGFR. Preclinical and phase I studies have shown activity with lapatinib in a number of cancers, including breast cancer, and the drug is well tolerated. The main known drug interactions are with paclitaxel and irinotecan. The most significant side-effects of lapatinib are diarrhea and adverse skin events. Rates of cardiotoxicity compare favorably with trastuzumab, a monoclonal antibody against HER-2. This paper focuses on lapatinib in advanced and metastatic breast cancer, which remains an important therapeutic challenge. Phase II and III studies show activity as monotherapy, and in combination with chemotherapy or hormonal agents. Results from these studies suggest that the main benefit from lapatinib is in the HER-2 positive breast cancer population. Combinations of lapatinib and trastuzumab are also being studied and show encouraging results, particularly in trastuzumab-refractory metastatic breast cancer. Lapatinib may have a specific role in treating HER-2 positive CNS metastases. The role of lapatinib as neoadjuvant therapy and in early breast cancer is also being evaluated.