Year: 2024
Type: article
Abstract: Cancer proteogenomics promises new insights into cancer biology and treatment efficacy by integrating genomics, transcriptomics and protein profiling including modifications by mass spectrometry (MS). A critical limitation is sample input requirements that exceed many sources of clinically important material. Here we report a proteogenomics approach for core biopsies using tissue-sparing specimen processing and microscaled proteomics. As a demonstration, we analyze core needle biopsies from ERBB2 positive breast cancers before and 48–72 h after initiating neoadjuvant trastuzumab-based chemotherapy. We show greater suppression of ERBB2 protein and both ERBB2 and mTOR target phosphosite levels in cases associated with pathological complete response, and identify potential causes of treatment resistance including the absence of ERBB2 amplification, insufficient ERBB2 activity for therapeutic sensitivity despite ERBB2 amplification, and candidate resistance mechanisms including androgen receptor signaling, mucin overexpression and an inactive immune microenvironment. The clinical utility and discovery potential of proteogenomics at biopsy-scale warrants further investigation.
DOI: 10.17615/rb11-7v56
Authors: Chan, D.W, Zhang, B, Ademuyiwa, F.O, Singh, P, Perou, C.M, Saltzman, A.B, Wen, B, Gillette, M.A, Satpathy, S, Miles, G, Mani, D.R, Dou, Y, Schiff, R, Holloway, K.R, Vasaikar, S.V, Kim, B.-J, Jacobs, S, Krug, K, Ellis, M.J, Jaehnig, E.J, Namai, N, Hyslop, T, Mutch, D, Gao, A, Ma, C, Hoog, J, Anurag, M, Malovannaya, A, Carr, S.A, Clauser, K.R, Rimawi, M.F, Huang, C, Watson, M.A
Institution: University of North Carolina at Chapel Hill
Language: English
Subfield: Spectroscopy
Field: Chemistry
Domain: Physical Sciences
Open Access status: green
Funders: Breast Cancer Research Foundation, Cancer Prevention and Research Institute of Texas, Washington University in St. Louis, University of Washington, Institute of Clinical and Translational Sciences, Broad Institute, Alvin J. Siteman Cancer Center, Georgia Clinical and Translational Science Alliance, National Institutes of Health, National Cancer Institute, National Center for Advancing Translational Sciences
Awards: G1252910802, G1389837536, G1661677298, G1699415014, G2195970601, G2358021521, G2824222223, G3455473179, Recruitment of Rising Stars, G4356369037, G4429321274, Recruitment of Established Investigators, G531517939, Center of Excellence for High Throughput Proteogenomic Characterization, G6120206497, MICROSCALED PROTEOGENOMICS FOR CANCER CLINICAL TRIALS, G7922605845, Integrated high throughput proteogenomic data analysis center for CPTAC, G8979049835, G9000006824, G9000037442, G9000043102, G9000086393, Cancer Center Support Grant
OpenAlex ID: W4400034853