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

The breast cancer drug lapatinib increases the sensitivity of colon cancer cells to apoptosis through a HER2- and EGFR-independent mechanism. Coaxing Colon Cancer Cells to an Easy Death In a utopian future, physicians will have a well-stocked arsenal from which to choose the ideal drug for every subtype of cancer. One essential weapon will be agents that trigger apoptosis in cancer cells, overriding their reluctance to die. These will include molecules that activate TRAIL (tumor necrosis factor–related apoptosis-inducing ligand) death receptors, which normally initiate the so-called extrinsic apoptotic pathway, causing cell death. Dolloff et al. have found a way to boost the ability of colon cancer cells to die in response to TRAIL, by pretreating with lapatinib, a drug already approved for use in breast cancer. The sensitizing effect results from actions of the drug other than its ability to inhibit HER2/EGFR (epidermal growth factor receptor family members), its targets in breast cancer. In a panel of TRAIL-resistant colon cancer cells, 2 days of pretreatment with lapatinib sensitized the cells to a subsequent 24-hour treatment with TRAIL, causing substantial caspase activation and cell death. This combined therapy could also suppress tumor growth in mice. But the effectiveness of TRAIL may be limited in the clinic because of its brief half-life. Of higher interest are the antibodies mapatumumab and lexatumumab, which target TRAIL death receptors and are currently being tested in clinical trials. Indeed, these therapeutic antibodies too induce apoptosis more readily after pretreatment of cancer cells with lapatinib. What does lapatinib do to coax these cells to die? Measurements of the levels of the death receptors themselves, DR4 and DR5, show that they are increased after lapatinib treatment via induction of the c-Jun N-terminal kinase (JNK)/c-Jun/activating protein–1 (AP-1) pathway. Although lapatinib was designed as an EGFR- and HER2-targeted agent, the authors suspected that it was not acting through these known targets to promote TRAIL receptor–induced apoptosis. The concentrations required were higher than needed for HER2/EGFR inhibition. Indeed, lapatinib up-regulated TRAIL death receptors and enhanced TRAIL sensitivity in cells that lack EGFR; moreover, the mere inhibition of EGFR and HER2 with other selective inhibitors was not sufficient to enhance TRAIL-induced cancer cell death. If confirmed by clinical validation, this newly described, non-EGFR/HER2–mediated action of lapatinib in sensitizing colon cancer cells to apoptotic stimuli will qualify this drug for a new place among anticancer munitions. Lapatinib, a dual HER2/EGFR (human epidermal growth factor receptor 2/epidermal growth factor receptor) inhibitor, is a recently approved targeted therapy for metastatic breast cancer. Because lapatinib enhances the efficacy of the chemotherapeutic agent capecitabine in breast cancer patients, we tested whether lapatinib also enhances the activity of anticancer agents in colorectal cancer. We found that lapatinib improved the proapoptotic effects of tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) and two TRAIL receptor agonists, the antibodies mapatumumab and lexatumumab. Tumors from mice treated with a combination of lapatinib and TRAIL exhibited more immunostaining for cleaved caspase-8, a marker of the extrinsic cell death pathway, than did tumors from mice treated with lapatinib or TRAIL alone. Furthermore, combination therapy suppressed tumor growth more effectively than either agent alone. Lapatinib up-regulated the proapoptotic TRAIL death receptors DR4 and DR5, leading to more efficient induction of apoptosis in the presence of TRAIL receptor agonists. This activity of lapatinib was independent of EGFR and HER2. The off-target induction of DR5 by lapatinib resulted from activation of the c-Jun amino-terminal kinase (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.