Proteomic Resistance Biomarkers for PI3K Inhibitor in Triple Negative Breast Cancer Patient-Derived Xenograft Models
Abstract
:Simple Summary
Abstract
1. Introduction
2. Results
2.1. Generation and Characterization of TNBC PDX Models
2.2. Tumor Growth Response to BKM120 in TNBC PDX Models
2.3. RPPA Analysis Indicating PI3K Pathway Inhibition by BKM120
2.4. Baseline Proteomic Analysis Reveals Potential Resistance Biomarkers to BKM120
2.5. Treatment-Induced Proteomic Changes Reveal Potential Resistance Biomarkers to BKM120
3. Discussion
4. Materials and Methods
4.1. Chemicals and Antibodies
4.2. Generation of PDX Models
4.3. Immunohistochemistry
4.4. mRNA Gene Expression Analysis Using Agilent 4X44K Arrays
4.5. Whole Exome Sequencing Analysis
4.6. Reverse Phase Protein Array (RPPA) and PI3K Signature Score
4.7. Treatments of Patient-Derived Triple Negative Breast Cancer Xenograft Models
4.8. In Vitro Cytotoxic Assay
4.9. Statistical Analysis
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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PDX ID | Selected Actionable Mutations and Significantly Mutated Genes | PI3K Pathway Alterations |
---|---|---|
WHIM2, 5 | PTCH2 p.W293S; JAK2 p.I166T; MAP3K8 p.P461L, TP53 p.Q167Tfs | AKT3 Amp |
WHIM3 | KRAS p.G13D; NF1 p.Q1775L | |
WHIM4 | TP53 p.E326Q, p.E285*, p.R175H; ALK p.R395H | PIK3CA amp |
WHIM6 | ||
WHIM10 | ||
WHIM12 | TP53 p.R248Q; PTPRJ p.K1017N; HRAS p.G12D; PIK3CA p.E109fs; PTEN p.T319* | PIK3CA p.V105_E109delinsT; PTEN p.T319* |
WHIM13 | TP53 p.C238Y; KIT p.D419H | |
WHIM14 | TP53 p.I195T, CSF1R p.N241K; NTRK3 p.T332M | |
WHIM21 | FGFR3 p.E135K, PTPRS p.P1506T; TP53 p.P151H | AKT1 Amp |
WHIM25 | TP53 p.R273H | |
WHIM29 | PTEN p.E284*, TP53 p.V216M | PTEN p.E284* |
WHIM30 | BRCA1 p.E1410* (germline); TP53 p.X125_splice site; ATM p.D126E; ATR p.M211T | |
WHIM31 | BRCA1 p.3604delA (germline); TP53 p.R342*, KRAS p.A134V; PIK3CG p.I287M | |
WHIM34 | TP53 p.R248W; PTEN p.D310G, GATA3 p.T421Rfs*55 | PTEN p.D310G |
WHIM36 | TP53 p.F134C; | |
WHIM48 | TP53 p.Y205H; MET p.R988C |
Protein Marker | SpearmanCorr2TGI | p Value |
---|---|---|
MMP9 | −0.70098 | 0.002347 |
EGFR | −0.64461 | 0.006396 |
Integrina5 | −0.57843 | 0.016803 |
Caspase 3 | 0.541667 | 0.026735 |
p-IkappaB (S32/36) | −0.5098 | 0.038642 |
RANKL | −0.48284 | 0.051624 |
p-HER3(Y1197) | −0.47304 | 0.057094 |
Caveolin | −0.46569 | 0.061477 |
CBP | −0.46324 | 0.062994 |
PI3Kp85 | −0.45588 | 0.067714 |
Bak | 0.443627 | 0.076168 |
Bcl.xL | −0.43873 | 0.079763 |
Vimentin | −0.43137 | 0.085389 |
KLF4 | −0.42892 | 0.087329 |
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Guo, Z.; Primeau, T.; Luo, J.; Zhang, C.; Sun, H.; Hoog, J.; Gao, F.; Huang, S.; Edwards, D.P.; Davies, S.R.; et al. Proteomic Resistance Biomarkers for PI3K Inhibitor in Triple Negative Breast Cancer Patient-Derived Xenograft Models. Cancers 2020, 12, 3857. https://doi.org/10.3390/cancers12123857
Guo Z, Primeau T, Luo J, Zhang C, Sun H, Hoog J, Gao F, Huang S, Edwards DP, Davies SR, et al. Proteomic Resistance Biomarkers for PI3K Inhibitor in Triple Negative Breast Cancer Patient-Derived Xenograft Models. Cancers. 2020; 12(12):3857. https://doi.org/10.3390/cancers12123857
Chicago/Turabian StyleGuo, Zhanfang, Tina Primeau, Jingqin Luo, Cynthia Zhang, Hua Sun, Jeremy Hoog, Feng Gao, Shixia Huang, Dean P. Edwards, Sherri R. Davies, and et al. 2020. "Proteomic Resistance Biomarkers for PI3K Inhibitor in Triple Negative Breast Cancer Patient-Derived Xenograft Models" Cancers 12, no. 12: 3857. https://doi.org/10.3390/cancers12123857