Use of protein pathway mapping of brain metastasis from breast and lung cancer patients to identify new therapeutic targets: A seed/soil study.

Abstract

10620 Background: Brain metastases are the most common fatal complication of systemic cancer, especially of lung (50%-60%) and breast (15%-20%) cancers. In this era of personalized therapy, there is a critical need to uncover the critical molecular targets for brain metastases, however little is known about what signaling pathways are actually activated in the context of the brain microenvironment. Using a unique study set of brain metastases from patients with breast or lung cancer along with a separate set of primary NSCLC tumors, functional broad-scale pathway activation mapping could be performed. Methods: Epitheliumfrom 89 frozen biopsy samples (10 breast and 32 lung metastasis; 47 primary lung cancer) were collected using Laser Capture Microdissection. The phosphorylation/activation of 128 key signaling proteins involved in important molecular pathways was measured using Reverse Phase Protein Microarray technology. Results: Brain metastasis from breast and lung cancer formed distinct pathway subgroups that consisted of amongst others, c-erbb2, AKT, mTOR, EGFR, SMAD, and ERK-p38 signaling. EGFR phosphorylation did not necessarily correlate with EGFR protein expression levels. Of 128 signaling analytes measured, 30 revealed significant differences in levels of activation/phosphorylation between breast and lung metastases to the brain and 58 were differently activated between lung to brain metastases and primary lung tumors (p < 0.05). Breast cancer metastases showed significantly (p < 0.05) higher activation of many components of the c-erbB2/IGFR-AKT pathway networks compared to lung cancer metastasis whereas lung cancer metastases to the brain exhibited higher relative levels of many members of the EGFR- ERK signaling network. Conclusions: Pathway activation mapping of brain metastasis demonstrates signaling activation portraits with both “seed” and “soil” components. These distinct activation groupings reveal both the heterogeneity of signaling networks in brain metastasis that would require a prior stratification to targeted therapies as well as the requirement of direct analysis of the metastatic lesion. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Theranostics Health Theranostics Health Theranostics Health