Therapies targeting the ERBB family members, EGFR and HER2, are commonly used for a wide range of epithelial cancers including lung, breast, colon and head and neck cancers. In a subset of these cancers, this provides substantial clinical benefit. Such cancers are unique in that they are "addicted" to ERBB signaling and either EGFR or HER2 controls critical growth and survival signaling pathways including PI3K/AKT, MAPK, and STAT. Previously, we and others observed that all cancer cells addicted to EGFR or HER2, are unique in that PI3K is activated by directly binding to tyrosine phosphorylated ERBB3, a kinase-dead ERBB family member (Engelman et al, PNAS, 2005). Thus, when these cancer cells are exposed to the appropriate ERBB inhibitor, ERBB3 phosphorylation is lost, PI3K and the other intracellular pathways are turned off, and the cancer cells undergo apoptosis. However, most, if not all patients, who initially develop a partial or complete response to an ERBB inhibitor will eventually develop progression of their cancer. Several groups including ours have found that a cancer becomes resistant to an ERBB inhibitor by finding a way to maintain PI3K/AKT signaling despite the presence of inhibitor. Recently, we modeled acquired resistance to EGFR kinase inhibitors by exposing EGFR-addicted cancer cell lines to increasing doses of inhibitor until the cells became resistant. In one of the resistant models, we found that the MET gene was amplified, and we validate this in lung cancer specimens that had become resistant to EGFR inhibitors (Engelman et al., Science, 2007). To our surprise, we found that the MET receptor tyrosine kinase caused resistance by maintaining phosphorylation of ERBB3 independently of EGFR and HER2. This was unexpected because previously only EGFR and HER2 were thought to be capable of phosphorylating ERBB3. Additionally, we found that MET signaling to ERBB3 was a pathway shared by all of the MET amplified cancer cell lines examined. When the gefitinib-resistant cells that developed MET amplification were treated with a combination of EGFR and MET inhibitors, there was obliteration of ERBB3 and AKT phosphorylation accompanied by marked cell death. This has spurred clinical trials testing a combination of MET and EGFR inhibitors for patients with acquired resistance to gefitinib or erlotinib. The finding that MET amplification activates ERBB3 phosphorylation independently of EGFR and HER2 suggests that it would be a potent resistance mechanism for other ERBB addicted cancers as well. In this grant application, we aim to determine if MET activation, via overexpression or ligand activation, maintains ERBB3/PI3K/AKT signaling and induces resistance to ERBB inhibitors in a broad range of EGFR and HER2 addicted cancers in vitro and in vivo. We will also determine if MET amplification is observed in patient cancer specimens that have developed resistance to ERBB targeted therapies. If MET amplification causes resistance in other ERBB driven cancers, this would immediately suggest diagnostic tests and therapeutic strategies for a wide range of cancers that become resistant to EGFR and HER2 directed therapies.
Metastatic lung, breast, colon and head and neck cancers are almost uniformly fatal and a very prominent cause of suffering in the United States and the rest of the world. Recently, therapies targeting the ERBB family proteins, EGFR and HER2, have been developed that effectively treat a subset of patients afflicted with these illnesses. Although these treatments are often initially effective, cancers invariably develop resistance to them. In this grant proposal, we aim to identify how these cancers become resistant so that we can design effective therapies to overcome this resistance and provide benefit to our patients.
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