Off-Target Lapatinib Activity Sensitizes Colon Cancer Cells Through TRAIL Death Receptor Up-Regulation

Abstract

Lapatinib, a HER2/EGFR inhibitor, is a recently approved targeted therapy for metastatic breast cancer. As lapatinib enhances the efficacy of the antimetabolite capecitabine in breast cancer patients, we lapatinib also enhance the activity of anti-cancer agents in colorectal cancer. We found that lapatinib the pro-apoptotic effects of Tumor necrosis factor-Related Apoptosis-Inducing Ligand (TRAIL) and TRAIL receptor antibodies mapatumumab and lexatumumab. Tumors from mice treated with lapatinibTRAIL exhibited more immunostaining for cleaved caspase-8, the extrinsic cell death pathway, tumors from mice treated with lapatinib or TRAIL alone. Furthermore, combination therapy suppressed tumor growth more effectively than treatment. apatinib up-the proapoptotic TRAIL death receptors DR4 and DR5, leading to more efficient induction of apoptosis in the presence of TRAIL receptor agonistsThis activity was independent of EGFR and HER2 off-target induction of DR5 by lapatinib activation of the JNK/c-Jun signaling axis. This activity of lapatinib on TRAIL death receptor expression and signaling may confer therapeutic benefit when increased doses of lapatinib are used in combination with TRAIL-receptor-activating agents.

The flavonolignan silibinin potentiates TRAIL-induced apoptosis in human colon adenocarcinoma and in derived TRAIL-resistant metastatic cells

“…The amount of dead cells remained below 30% after 48 h of treatment in both cell lines. TRAIL alone induced a percentage of cell death of about 30 % in SW480 cells while the percentage of TRAILinduced cell death in SW620 cells remained below 10 % reflecting the TRAIL-resistance of the metastatic SW620 cells [27]. The combination of silibinin (300 lM) and TRAIL significantly increased the amount of dead cells in both cell lines to about 70 % after 24 h and 80 % after 48 h of treatment.…”

Mitomycin C potentiates TRAIL-induced apoptosis through p53-independent upregulation of death receptors

“…It has been reported that DNA-damaging agents and small-molecule inhibitors effectively sensitize cancer cells to TRAIL. 10,13,14 Mitomycin-C (MMC) is an antibiotic that has demonstrated antitumor activity in preclinical and clinical studies and is widely used to treat various cancers. MMC is known to act synergistically with capecitabine and irinotecan.…”

Targeting TRAIL in the treatment of cancer: new developments

“…Lapatinib is another candidate to potentiate the sensitivity of cancer cells to the TRAIL pathway by an off-target effect in colorectal cancer [54]. Agents that can up-regulate the effector of apoptosis can be another strategy.…”