Microscaled proteogenomic methods for precision oncology

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 biopsyscale warrants further investigation.

Proteomic patterns associated with response to breast cancer neoadjuvant treatment

“…Evaluation of 1,010 treatment-naïve samples from the TCGA breast cancer provisional dataset showed that high mRNA levels of PYCR1 were also significantly associated with poor progression-free survival (Appendix Fig S4G). In addition, a proteomic dataset of drug response in ten patients (Satpathy et al, 2020) showed that similar to our observation, PYCR1 was significantly downregulated in samples from complete responders taken 72 h post-treatment and was unaltered in non-responders (Appendix Fig S4H). .…”

“…MS-based clinical proteomics of breast cancer has focused in recent years on cancer classification, showing protein networks associated with each subtype, with driver mutations and was able to challenge the RNA-based classification (Mertins et al, 2016;Tyanova et al, 2016a;Yanovich et al, 2018). Recently, proteogenomic analysis of breast cancer treatment response showed proteins associated with Herceptin resistance in a small patient cohort (Satpathy et al, 2020). We hypothesized that an untargeted, proteomic approach has the potential to unravel novel pathways of neoadjuvant chemotherapy response.…”

Which path to follow? Utilizing proteomics to improve therapy choices for breast cancer patients

“…Proteomics assessment of breast cancer subtypes using mass spectrometry (MS) offers additional and complementary information to that of the RPPA platform, given that MS covers a more global profile of protein markers but has a lower sensitivity particularly for regulatory post-translational events. Recent development of a microscale proteogenomic approach demonstrated the feasibility of deep proteogenomic profiling in core biopsies with sizes at least fivefold smaller than the requirement from the Clinical Proteomic Tumor Analysis Consortium [23]. Unsupervised clinical proteomics MS-based clustering conducted by our group and others displayed limited overlap with mRNA-guided classifications.…”

Proteomic approaches for characterizing renal cell carcinoma

“…Potentially illustrated in these studies is the major hurdle in ITH-based proteome characterization, specifically the limited amount of material available from individual tumors available for proteomic analysis. As genomic-and transcriptomic-based single cell analyses become more widespread [127], complementary mass spectrometry-based proteomic approaches that enable a relatively deep proteomic characterization of tissues using minimal sample input or single cells will be further developed [128][129][130][131], and will be applicable to explore this area of RCC biology.…”