Microscaled Proteogenomic Methods for Precision Oncology

Satpathy, S.; Jaehnig, E. J.; Krug, K.; Kim, B.-J.; Saltzman, A. B.; Chan, D.; Holloway, K. R.; Anurag, M.; Huang, C.; Singh, P.; Gao, A.; Namai, N.; Dou, Y.; Wen, B.; Vasaikar, S.; Mutch, D.; Watson, M.; Ma, C.; Ademuyiwa, F. O.; Rimawi, M.; Schiff, R.; Hoog, J.; Jacobs, S.; Malovannaya, A.; Hyslop, T.; Clauser, K. C.; Mani, D. R.; Perou, C.; Miles, G.; Zhang, B.; Gillette, M. A.; Carr, S. A.; Ellis, M. J.

doi:10.1101/796318

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bioRxiv · 10.1101/796318

Microscaled Proteogenomic Methods for Precision Oncology

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Abstract

Cancer proteogenomics integrates genomics, transcriptomics and mass spectrometry (MS)-based proteomics to gain insights into cancer biology and treatment efficacy. A proteogenomics approach was therefore developed for frozen core biopsies using tissue-sparing specimen processing with a \"microscaled\" proteomics workflow. For technical proof-of-principle, biopsies from ERBB2 positive breast cancers before and 48-72 hours after the first dose of neoadjuvant trastuzumab-based chemotherapy were analyzed. ERBB2 protein and phosphosite levels, as well as mTOR target phosphosites, were significantly more suppressed upon treatment in cases associated with pathological complete response, suggesting MS-based pharmacodynamics is achievable. Furthermore, integrated analyses indicated potential causes of treatment resistance including the absence of ERBB2 amplification (false-ERBB2 positive) and insufficient ERBB2 activity for therapeutic sensitivity despite ERBB2 amplification (pseudo-ERBB2 positive). Candidate resistance features in true-ERBB2+ cases, including androgen receptor signaling, mucin expression and an inactive immune microenvironment were observed. Thus, proteogenomic analysis of needle core biopsies is feasible and clinical utility should be investigated.

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Satpathy, S., Jaehnig, E. J., Krug, K., Kim, B.-J., Saltzman, A. B., Chan, D., Holloway, K. R., Anurag, M., Huang, C., Singh, P., Gao, A., Namai, N., Dou, Y., Wen, B., Vasaikar, S., Mutch, D., Watson, M., Ma, C., Ademuyiwa, F. O., Rimawi, M., Schiff, R., Hoog, J., Jacobs, S., Malovannaya, A., Hyslop, T., Clauser, K. C., Mani, D. R., Perou, C., Miles, G., Zhang, B., Gillette, M. A., Carr, S. A., Ellis, M. J.. 2019-10-08. Microscaled Proteogenomic Methods for Precision Oncology. https://doi.org/10.1101/796318

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