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.
|Hata, Aaron N; Niederst, Matthew J; Archibald, Hannah L et al. (2016) Tumor cells can follow distinct evolutionary paths to become resistant to epidermal growth factor receptor inhibition. Nat Med 22:262-9|
|Sequist, Lecia V; Piotrowska, Zofia; Niederst, Matthew J et al. (2016) Osimertinib Responses After Disease Progression in Patients Who Had Been Receiving Rociletinib. JAMA Oncol 2:541-3|
|Piotrowska, Zofia; Drapkin, Benjamin; Engelman, Jeffrey A et al. (2016) Plasma T790M Result Alters Treatment Options in a Previously T790 Wild-Type EGFR-Mutant Lung Cancer. J Thorac Oncol 11:e95-e97|
|Piotrowska, Zofia; Niederst, Matthew J; Karlovich, Chris A et al. (2015) Heterogeneity Underlies the Emergence of EGFRT790 Wild-Type Clones Following Treatment of T790M-Positive Cancers with a Third-Generation EGFR Inhibitor. Cancer Discov 5:713-22|
|Hata, Aaron N; Engelman, Jeffrey A; Faber, Anthony C (2015) The BCL2 Family: Key Mediators of the Apoptotic Response to Targeted Anticancer Therapeutics. Cancer Discov 5:475-87|
|Faber, Anthony C; Farago, Anna F; Costa, Carlotta et al. (2015) Assessment of ABT-263 activity across a cancer cell line collection leads to a potent combination therapy for small-cell lung cancer. Proc Natl Acad Sci U S A 112:E1288-96|
|Niederst, Matthew J; Hu, Haichuan; Mulvey, Hillary E et al. (2015) The Allelic Context of the C797S Mutation Acquired upon Treatment with Third-Generation EGFR Inhibitors Impacts Sensitivity to Subsequent Treatment Strategies. Clin Cancer Res 21:3924-33|
|Costa, Carlotta; Ebi, Hiromichi; Martini, Miriam et al. (2015) Measurement of PIP3 levels reveals an unexpected role for p110? in early adaptive responses to p110?-specific inhibitors in luminal breast cancer. Cancer Cell 27:97-108|
|Niederst, Matthew J; Sequist, Lecia V; Poirier, John T et al. (2015) RB loss in resistant EGFR mutant lung adenocarcinomas that transform to small-cell lung cancer. Nat Commun 6:6377|
|Oser, Matthew G; Niederst, Matthew J; Sequist, Lecia V et al. (2015) Transformation from non-small-cell lung cancer to small-cell lung cancer: molecular drivers and cells of origin. Lancet Oncol 16:e165-72|
Showing the most recent 10 out of 45 publications