PMID- 37587913
OWN - NLM
STAT- MEDLINE
DCOM- 20230818
LR  - 20230820
IS  - 2767-9764 (Electronic)
IS  - 2767-9764 (Linking)
VI  - 3
IP  - 8
DP  - 2023 Aug
TI  - Kinase Inhibitor Pulldown Assay Identifies a Chemotherapy Response Signature in 
      Triple-negative Breast Cancer Based on Purine-binding Proteins.
PG  - 1551-1563
LID - 10.1158/2767-9764.CRC-22-0501 [doi]
AB  - Triple-negative breast cancer (TNBC) constitutes 10%-15% of all breast tumors. 
      The current standard of care is multiagent chemotherapy, which is effective in 
      only a subset of patients. The original objective of this study was to deploy a 
      mass spectrometry (MS)-based kinase inhibitor pulldown assay (KIPA) to identify 
      kinases elevated in non-pCR (pathologic complete response) cases for therapeutic 
      targeting. Frozen optimal cutting temperature compound-embedded core needle 
      biopsies were obtained from 43 patients with TNBC before docetaxel- and 
      carboplatin-based neoadjuvant chemotherapy. KIPA was applied to the native tumor 
      lysates that were extracted from samples with high tumor content. Seven percent 
      of all identified proteins were kinases, and none were significantly associated 
      with lack of pCR. However, among a large population of "off-target" 
      purine-binding proteins (PBP) identified, seven were enriched in pCR-associated 
      samples (P < 0.01). In orthogonal mRNA-based TNBC datasets, this seven-gene "PBP 
      signature" was associated with chemotherapy sensitivity and favorable clinical 
      outcomes. Functional annotation demonstrated IFN gamma response, nuclear import 
      of DNA repair proteins, and cell death associations. Comparisons with standard 
      tandem mass tagged-based discovery proteomics performed on the same samples 
      demonstrated that KIPA-nominated pCR biomarkers were unique to the platform. KIPA 
      is a novel biomarker discovery tool with unexpected utility for the 
      identification of PBPs related to cytotoxic drug response. The PBP signature has 
      the potential to contribute to clinical trials designed to either escalate or 
      de-escalate therapy based on pCR probability. SIGNIFICANCE: The identification of 
      pretreatment predictive biomarkers for pCR in response to neoadjuvant 
      chemotherapy would advance precision treatment for TNBC. To complement standard 
      proteogenomic discovery profiling, a KIPA was deployed and unexpectedly 
      identified a seven-member non-kinase PBP pCR-associated signature. Individual 
      members served diverse pathways including IFN gamma response, nuclear import of 
      DNA repair proteins, and cell death.
CI  - (c) 2023 The Authors; Published by the American Association for Cancer Research.
FAU - Wang, Junkai
AU  - Wang J
AUID- ORCID: 0000-0003-4782-5790
AD  - Lester and Sue Smith Breast Center and Dan L. Duncan Comprehensive Cancer Center, 
      Baylor College of Medicine, Houston, Texas.
AD  - Department of Molecular and Cellular Biology, Baylor College of Medicine, 
      Houston, Texas.
FAU - Saltzman, Alexander B
AU  - Saltzman AB
AUID- ORCID: 0000-0003-4166-9555
AD  - Mass Spectrometry Proteomics Core, Advanced Technology Cores, Baylor College of 
      Medicine, Houston, Texas.
FAU - Jaehnig, Eric J
AU  - Jaehnig EJ
AUID- ORCID: 0000-0001-9618-6011
AD  - Lester and Sue Smith Breast Center and Dan L. Duncan Comprehensive Cancer Center, 
      Baylor College of Medicine, Houston, Texas.
FAU - Lei, Jonathan T
AU  - Lei JT
AUID- ORCID: 0000-0002-0209-8051
AD  - Lester and Sue Smith Breast Center and Dan L. Duncan Comprehensive Cancer Center, 
      Baylor College of Medicine, Houston, Texas.
FAU - Malovannaya, Anna
AU  - Malovannaya A
AUID- ORCID: 0000-0003-2953-6485
AD  - Mass Spectrometry Proteomics Core, Advanced Technology Cores, Baylor College of 
      Medicine, Houston, Texas.
AD  - Department of Biochemistry and Molecular Biology, Baylor College of Medicine, 
      Houston, Texas.
FAU - Holt, Matthew V
AU  - Holt MV
AUID- ORCID: 0000-0002-1418-6139
AD  - Lester and Sue Smith Breast Center and Dan L. Duncan Comprehensive Cancer Center, 
      Baylor College of Medicine, Houston, Texas.
FAU - Young, Meggie N
AU  - Young MN
AUID- ORCID: 0000-0003-2684-7317
AD  - Department of Biochemistry and Molecular Biology, Baylor College of Medicine, 
      Houston, Texas.
FAU - Rimawi, Mothaffar F
AU  - Rimawi MF
AUID- ORCID: 0000-0002-4284-5656
AD  - Lester and Sue Smith Breast Center and Dan L. Duncan Comprehensive Cancer Center, 
      Baylor College of Medicine, Houston, Texas.
FAU - Ademuyiwa, Foluso O
AU  - Ademuyiwa FO
AUID- ORCID: 0000-0002-6766-2258
AD  - Siteman Comprehensive Cancer Center and Washington University School of Medicine, 
      St. Louis, Missouri.
FAU - Anurag, Meenakshi
AU  - Anurag M
AUID- ORCID: 0000-0003-4379-5192
AD  - Lester and Sue Smith Breast Center and Dan L. Duncan Comprehensive Cancer Center, 
      Baylor College of Medicine, Houston, Texas.
AD  - Department of Medicine, Baylor College of Medicine, Houston, Texas.
FAU - Kim, Beom-Jun
AU  - Kim BJ
AUID- ORCID: 0000-0003-3109-8170
AD  - Lester and Sue Smith Breast Center and Dan L. Duncan Comprehensive Cancer Center, 
      Baylor College of Medicine, Houston, Texas.
AD  - AstraZeneca, Gaithersburg, Maryland.
FAU - Ellis, Matthew J
AU  - Ellis MJ
AUID- ORCID: 0000-0002-8467-8534
AD  - Lester and Sue Smith Breast Center and Dan L. Duncan Comprehensive Cancer Center, 
      Baylor College of Medicine, Houston, Texas.
AD  - AstraZeneca, Gaithersburg, Maryland.
LA  - eng
GR  - K12 CA167540/CA/NCI NIH HHS/United States
GR  - P30 CA125123/CA/NCI NIH HHS/United States
GR  - T32 CA203690/CA/NCI NIH HHS/United States
GR  - P50 CA186784/CA/NCI NIH HHS/United States
GR  - U01 CA214125/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20230815
PL  - United States
TA  - Cancer Res Commun
JT  - Cancer research communications
JID - 9918281580506676
RN  - 0 (Carrier Proteins)
RN  - 0 (Antineoplastic Agents)
RN  - 15H5577CQD (Docetaxel)
RN  - 0 (Purines)
SB  - IM
MH  - Humans
MH  - Carrier Proteins
MH  - *Triple Negative Breast Neoplasms/drug therapy
MH  - *Antineoplastic Agents/pharmacology
MH  - Docetaxel
MH  - Purines
PMC - PMC10426551
EDAT- 2023/08/17 06:43
MHDA- 2023/08/18 06:43
PMCR- 2023/08/15
CRDT- 2023/08/17 03:54
PHST- 2022/12/09 00:00 [received]
PHST- 2023/04/10 00:00 [revised]
PHST- 2023/06/21 00:00 [accepted]
PHST- 2023/08/18 06:43 [medline]
PHST- 2023/08/17 06:43 [pubmed]
PHST- 2023/08/17 03:54 [entrez]
PHST- 2023/08/15 00:00 [pmc-release]
AID - CRC-22-0501 [pii]
AID - 10.1158/2767-9764.CRC-22-0501 [doi]
PST - epublish
SO  - Cancer Res Commun. 2023 Aug 15;3(8):1551-1563. doi: 
      10.1158/2767-9764.CRC-22-0501. eCollection 2023 Aug.