Non-Small Cell Lung Cancer
MM-121 and erlotinib-containing regimen
Overexpression and mutation of the Epidermal Growth Factor Receptor (EGFR) has been implicated in the development and progression of lung cancers. Unregulated EGFR signaling results in increased cell migration, adhesion, and proliferation, characteristics important for tumorigenesis. Anti-EGFR therapies such as erlotinib, a reversible tyrosine kinase inhibitor, are designed to block the phosphorylation events resulting in EGFR activation, thereby inhibiting the associated growth and survival response.
Although EGFR-targeted therapies can be effective at treating EGFR-driven cancers, resistance invariably develops in patients. One mechanism by which this occurs is through the compensatory activation of HER3 and the associated pro-survival signaling pathways. This adaption provides an opportunity for the cancer cell to continue to grow despite effective EGFR inhibition. HER3 is a key signaling protein in many types of cancers. Heregulin (HRG)-induced signaling through HER3 activates pathways promoting the development, growth, and progression of cancer.
Compensatory activation of HER3 is believed to be a central mechanism by which cancer cells acquire resistance to targeted therapies as well as many chemotherapies (Schoeberl et al., 2010). MM-121 is a HER3-targeted antibody that functions by inhibiting ligand-induced signaling through HER3 (Schoeberl et al., 2010; Schoeberl et al., 2009). This mechanism is designed to inhibit cancer growth directly, restore sensitivity to drugs to which a tumor has become resistant, and delay the development of resistance to other agents.
MM-121 is being tested clinically in combination with erlotinib in advanced non-small cell lung cancer (NSCLC) patients. It is our hypothesis that MM-121 has the potential to help many patients in multiple indications. To continue our learning and to identify new ways that this treatment can benefit patients, we are analyzing potential biomarkers in connection with our MM-121 clinical trials. Through this approach, we hope to generate additional knowledge on how ErbB3 signaling affects response to therapy, and then apply this understanding to identify patients that will most likely benefit from treatment regimens that include MM-121.