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Proteogenomic profiling of lung adenocarcinoma reveals therapeutic targets for precision medicine

Year 2024, Volume: 13 Issue: 4, 1545 - 1552, 15.10.2024
https://doi.org/10.28948/ngumuh.1542153

Abstract

Lung cancer is the top cause of cancer-related fatalities worldwide, impacting both men and women. A major challenge is its frequent diagnosis at advanced stages, which limits treatment options. While genomic and transcriptomic analyses have traditionally been used to identify potential drug targets, there remains an unexplored potential in targeting protein-level anomalies. This study systematically investigates the proteomic landscape of 109 primary lung adenocarcinoma (LUAD) tumors using comprehensive mass-spectrometry (MS) proteomics data. By focusing on kinases, the key actors in oncogenic signaling pathways, we aim to find new therapeutic targets for LUAD. Through intricate analyses encompassing tumor-normal differentials and inter-tumor variations, our study identifies notable overexpressed targets, including PLAU, MET, ERBB2, EGFR, PDK1 kinases, and THBS2, CRABP2, INPP4B proteins, many of which present no evidence of transcriptomic alteration. Several targets we identified through proposed approaches have corresponding inhibitor drugs, including ERBB2 kinase (Afatinib) and VEGF-A protein (Bevacizumab). Our findings validate known therapeutic markers in lung cancer and reveal candidate protein targets specific to LUAD, underscoring the efficacy of proteomic methodologies in advancing precision medicine for cancer.

References

  • H. Sung, J. Ferlay, R.L. Siegel, M. Laversanne, I. Soerjomataram, A. Jemal, F. Bray, Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA: a cancer journal for clinicians, 71(3), 209–249, 2021. https://doi.org/10.3322/caac.21660.
  • R. Ruiz-Cordero and W. P. Devine, Targeted therapy and checkpoint immunotherapy in lung cancer. Surgical pathology clinics, 13(1), 1, 17–33, 2020. https://doi.org/110.1016/j.path.2019.11.002.
  • C. Swanton and R. Govindan, Clinical implications of genomic discoveries in lung cancer. New England Journal of Medicine, 374(19),19, 1864–73, 2016. https://doi.org/10.1056/NEJMra1504688.
  • K.-L. Huang et al. Proteogenomic integration reveals therapeutic targets in breast cancer xenografts. Nature Communications, 8, 14864, 2017. https://doi.org/ 10.1038/ncomms14864
  • K.-L. Huang et al., Spatially interacting phosphorylation sites and mutations in cancer. Nature Communications, 12(1), 1, 2313, 2021. https://doi.org/10.1038/s41467-021-22481-w.
  • K.-L. Huang et al., Regulated phosphosignaling associated with breast cancer subtypes and druggability. Molecular & Cellular Proteomics, 18(8), 1630–1650, 2019. https://doi.org/10.1074/ mcp.RA118.001243.
  • M. J. Ellis et al., Connecting genomic alterations to cancer biology with proteomics: the NCI clinical proteomic tumor analysis consortium. Cancer Discovery, 3(10), 1108–12, 2013. https://doi.org/10.1158/2159-8290.CD-13-0219.
  • K. V Ruggles et al., Methods, tools and current perspectives in proteogenomics. Molecular & Cellular Proteomics, 16(6), 959–981, 2017. https://doi.org/ 10.1074/mcp.MR117.000024.
  • A. Elmas, S. Tharakan, S. Jaladanki, M. D. Galsky, T. Liu, and K.-L. Huang, Pan-cancer proteogenomic investigations identify post-transcriptional kinase targets. Communications Biology, 4(1), 1112, 2021. https://doi.org/10.1038/s42003-021-02636-7.
  • M. A. Gillette et al., Proteogenomic characterization reveals therapeutic vulnerabilities in lung adenocarcinoma. Cell, 182(1), 200-225, 2020. https://doi.org/10.1016/j.cell.2020.06.013.
  • K. C. Cotto et al., DGIdb 3.0: a redesign and expansion of the drug-gene interaction database. Nucleic Acids Research, 46(D1), D1068–D1073, 2018. https://doi.org/10.1093/nar/gkx1143.
  • F. Sanchez-Vega et al., Oncogenic signaling pathways in the cancer genome atlas.,” Cell, 173(2), 321-337.e10, 2018. https://doi.org/10.1016/ j.cell.2018.03.035
  • M. E. Ritchie et al., Limma powers differential expression analyses for RNA-sequencing and microarray studies. Nucleic Acids Res, 43(7), e47, 2015. https://doi.org/10.1093/nar/gkv007.
  • J. I. Wu, Y. P. Lin, C. W. Tseng, H. J. Chen, and L. H. Wang, Crabp2 Promotes Metastasis of Lung Cancer Cells via HuR and Integrin β1/FAK/ERK Signaling. Scientific Reports, 9(1), 2019. https://doi.org/10.1038/ s41598-018-37443-4.
  • A. C. Garrido-Castro and E. Felip, HER2 driven non-small cell lung cancer (NSCLC): potential therapeutic approaches. Translational Lung Cancer Research, 2(2), 122–7, 2013.https://doi.org/10.3978/j.issn.2218-6751.2013.02.02.
  • B. Piperdi, A. Merla, and R. Perez-Soler, Targeting angiogenesis in squamous non-small cell lung cancer. Drugs, 74(4), 403–13, 2014. https://doi.org/10.1007/ s40265-014-0182-z.
  • P. Li, S. Zhao, and Y. Hu, SFRP2 modulates non small cell lung cancer A549 cell apoptosis and metastasis by regulating mitochondrial fission via Wnt pathways. Molecular Medicine Reports, 20(2), 1925–1932, 2019. https://doi.org/10.3892/mmr.2019.10393.
  • M. Montagner et al., Crosstalk with lung epithelial cells regulates Sfrp2-mediated latency in breast cancer dissemination. Nature Cell Biology, 22(3), 289–296, 2020.https://doi.org/10.1038/s41556-020-0474-3.
  • Y. Sun et al., Loss of tumor suppressor inositol polyphosphate 4-phosphatase type B impairs DNA double-strand break repair by destabilization of DNA tethering protein Rad50. Cell Death & Disease, 11(4), 292, 2020. https://doi.org/10.1038/s41419-020-2491-3.
  • Y. Bao, E. Yan, and N. Wang, Evaluation of GREM1 and THBS2 as prognostic markers in in non-small cell lung cancer. Journal of Cancer Research and Clinical Oncology, 149(10), 7849–7856, 2023. https://doi.org/10.1007/s00432-023-04746-7.
  • N. Coleman, L. Hong, J. Zhang, J. Heymach, D. Hong, and X. Le, Beyond epidermal growth factor receptor: MET amplification as a general resistance driver to targeted therapy in oncogene-driven non-small-cell lung cancer. ESMO Open, 6(6), 100319, 2021. https://doi.org/10.1016/j.esmoop.2021.100319.
  • P. Ning et al., PLAU plays a functional role in driving lung squamous cell carcinoma metastasis. Genes & Diseases, 11(2), 554–557, 2024. https://doi.org/ 10.1016/j.gendis.2023.04.010.
  • T. Liu and H. Yin, PDK1 promotes tumor cell proliferation and migration by enhancing the Warburg effect in non-small cell lung cancer. Oncology Reports, 37(1), 193–200, 2017. https://doi.org/10.3892/ or.2016.5253.
  • J. Barretina et al., The cancer cell line encyclopedia enables predictive modelling of anticancer drug sensitivity. Nature, 483(7391), 603–7, 2012. https://doi.org/10.1038/nature11003.
  • S. K. Jaladanki, A. Elmas, G. S. Malave, and K.-L. Huang, “Genetic dependency of Alzheimer’s disease-associated genes across cells and tissue types. Scientific Reports, 11(1), 12107, 2021. https://doi.org/10.1038/ s41598-021-91713-2.

Akciğer adenokarsinomunun proteogenomik analizi: hassas tıp için terapötik hedeflerin belirlenmesi

Year 2024, Volume: 13 Issue: 4, 1545 - 1552, 15.10.2024
https://doi.org/10.28948/ngumuh.1542153

Abstract

Akciğer kanseri, dünya genelinde kanserle ilişkili ölümlerin başlıca nedeni olup, hem erkekleri hem de kadınları etkilemektedir. En büyük zorluklardan biri, genellikle hastalığın ileri evrelerinde teşhis edilmesidir; bu da tedavi seçeneklerini kısıtlamaktadır. Genomik ve transkriptomik analizler geleneksel olarak potansiyel ilaç hedeflerini belirlemede kullanılmıştır; ancak protein düzeyindeki anormallikleri hedeflemekte henüz keşfedilmemiş bir potansiyel bulunmaktadır. Bu çalışma, 109 birincil akciğer adenokarsinomu (LUAD) tümörünün proteomik profilini kapsamlı kütle spektrometrisi (MS) verileri kullanarak sistematik bir şekilde incelemektedir. Onkogenik sinyal yolarında kritik rol oynayan kinazlara odaklanarak, LUAD için yeni terapötik hedefler bulmayı amaçlıyoruz. Tümör-normal farklılıkları ve tümörler arası varyasyonları içeren ayrıntılı analizler sonucunda, PLAU, MET, ERBB2, EGFR, PDK1 kinazları ve THBS2, CRABP2, INPP4B proteinleri gibi önemli aşırı ekspres edilen hedefler belirlenmiştir. Bu hedeflerin çoğunda transkriptomik değişim kanıtı bulunmamaktadır. Önerilen yaklaşımlar aracılığıyla belirlediğimiz bazı hedefler için mevcut inhibitör ilaçlar geliştirilmiştir, ERBB2 kinazı (Afatinib) ve VEGF-A proteini (Bevacizumab) gibi. Bulgularımız, akciğer kanserindeki bilinen terapötik belirteçleri doğrulamakta ve LUAD’e özgü aday protein hedeflerini ortaya koyarak, proteomik yöntemlerin kanser tedavisinde kişiselleştirilmiş tıbbın ilerletilmesindeki etkinliğini vurgulamaktadır.

References

  • H. Sung, J. Ferlay, R.L. Siegel, M. Laversanne, I. Soerjomataram, A. Jemal, F. Bray, Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA: a cancer journal for clinicians, 71(3), 209–249, 2021. https://doi.org/10.3322/caac.21660.
  • R. Ruiz-Cordero and W. P. Devine, Targeted therapy and checkpoint immunotherapy in lung cancer. Surgical pathology clinics, 13(1), 1, 17–33, 2020. https://doi.org/110.1016/j.path.2019.11.002.
  • C. Swanton and R. Govindan, Clinical implications of genomic discoveries in lung cancer. New England Journal of Medicine, 374(19),19, 1864–73, 2016. https://doi.org/10.1056/NEJMra1504688.
  • K.-L. Huang et al. Proteogenomic integration reveals therapeutic targets in breast cancer xenografts. Nature Communications, 8, 14864, 2017. https://doi.org/ 10.1038/ncomms14864
  • K.-L. Huang et al., Spatially interacting phosphorylation sites and mutations in cancer. Nature Communications, 12(1), 1, 2313, 2021. https://doi.org/10.1038/s41467-021-22481-w.
  • K.-L. Huang et al., Regulated phosphosignaling associated with breast cancer subtypes and druggability. Molecular & Cellular Proteomics, 18(8), 1630–1650, 2019. https://doi.org/10.1074/ mcp.RA118.001243.
  • M. J. Ellis et al., Connecting genomic alterations to cancer biology with proteomics: the NCI clinical proteomic tumor analysis consortium. Cancer Discovery, 3(10), 1108–12, 2013. https://doi.org/10.1158/2159-8290.CD-13-0219.
  • K. V Ruggles et al., Methods, tools and current perspectives in proteogenomics. Molecular & Cellular Proteomics, 16(6), 959–981, 2017. https://doi.org/ 10.1074/mcp.MR117.000024.
  • A. Elmas, S. Tharakan, S. Jaladanki, M. D. Galsky, T. Liu, and K.-L. Huang, Pan-cancer proteogenomic investigations identify post-transcriptional kinase targets. Communications Biology, 4(1), 1112, 2021. https://doi.org/10.1038/s42003-021-02636-7.
  • M. A. Gillette et al., Proteogenomic characterization reveals therapeutic vulnerabilities in lung adenocarcinoma. Cell, 182(1), 200-225, 2020. https://doi.org/10.1016/j.cell.2020.06.013.
  • K. C. Cotto et al., DGIdb 3.0: a redesign and expansion of the drug-gene interaction database. Nucleic Acids Research, 46(D1), D1068–D1073, 2018. https://doi.org/10.1093/nar/gkx1143.
  • F. Sanchez-Vega et al., Oncogenic signaling pathways in the cancer genome atlas.,” Cell, 173(2), 321-337.e10, 2018. https://doi.org/10.1016/ j.cell.2018.03.035
  • M. E. Ritchie et al., Limma powers differential expression analyses for RNA-sequencing and microarray studies. Nucleic Acids Res, 43(7), e47, 2015. https://doi.org/10.1093/nar/gkv007.
  • J. I. Wu, Y. P. Lin, C. W. Tseng, H. J. Chen, and L. H. Wang, Crabp2 Promotes Metastasis of Lung Cancer Cells via HuR and Integrin β1/FAK/ERK Signaling. Scientific Reports, 9(1), 2019. https://doi.org/10.1038/ s41598-018-37443-4.
  • A. C. Garrido-Castro and E. Felip, HER2 driven non-small cell lung cancer (NSCLC): potential therapeutic approaches. Translational Lung Cancer Research, 2(2), 122–7, 2013.https://doi.org/10.3978/j.issn.2218-6751.2013.02.02.
  • B. Piperdi, A. Merla, and R. Perez-Soler, Targeting angiogenesis in squamous non-small cell lung cancer. Drugs, 74(4), 403–13, 2014. https://doi.org/10.1007/ s40265-014-0182-z.
  • P. Li, S. Zhao, and Y. Hu, SFRP2 modulates non small cell lung cancer A549 cell apoptosis and metastasis by regulating mitochondrial fission via Wnt pathways. Molecular Medicine Reports, 20(2), 1925–1932, 2019. https://doi.org/10.3892/mmr.2019.10393.
  • M. Montagner et al., Crosstalk with lung epithelial cells regulates Sfrp2-mediated latency in breast cancer dissemination. Nature Cell Biology, 22(3), 289–296, 2020.https://doi.org/10.1038/s41556-020-0474-3.
  • Y. Sun et al., Loss of tumor suppressor inositol polyphosphate 4-phosphatase type B impairs DNA double-strand break repair by destabilization of DNA tethering protein Rad50. Cell Death & Disease, 11(4), 292, 2020. https://doi.org/10.1038/s41419-020-2491-3.
  • Y. Bao, E. Yan, and N. Wang, Evaluation of GREM1 and THBS2 as prognostic markers in in non-small cell lung cancer. Journal of Cancer Research and Clinical Oncology, 149(10), 7849–7856, 2023. https://doi.org/10.1007/s00432-023-04746-7.
  • N. Coleman, L. Hong, J. Zhang, J. Heymach, D. Hong, and X. Le, Beyond epidermal growth factor receptor: MET amplification as a general resistance driver to targeted therapy in oncogene-driven non-small-cell lung cancer. ESMO Open, 6(6), 100319, 2021. https://doi.org/10.1016/j.esmoop.2021.100319.
  • P. Ning et al., PLAU plays a functional role in driving lung squamous cell carcinoma metastasis. Genes & Diseases, 11(2), 554–557, 2024. https://doi.org/ 10.1016/j.gendis.2023.04.010.
  • T. Liu and H. Yin, PDK1 promotes tumor cell proliferation and migration by enhancing the Warburg effect in non-small cell lung cancer. Oncology Reports, 37(1), 193–200, 2017. https://doi.org/10.3892/ or.2016.5253.
  • J. Barretina et al., The cancer cell line encyclopedia enables predictive modelling of anticancer drug sensitivity. Nature, 483(7391), 603–7, 2012. https://doi.org/10.1038/nature11003.
  • S. K. Jaladanki, A. Elmas, G. S. Malave, and K.-L. Huang, “Genetic dependency of Alzheimer’s disease-associated genes across cells and tissue types. Scientific Reports, 11(1), 12107, 2021. https://doi.org/10.1038/ s41598-021-91713-2.
There are 25 citations in total.

Details

Primary Language English
Subjects Semi- and Unsupervised Learning, Biomedical Sciences and Technology, Biomedical Therapy
Journal Section Research Articles
Authors

Abdülkadir Elmas 0000-0002-7999-5770

Early Pub Date October 8, 2024
Publication Date October 15, 2024
Submission Date September 3, 2024
Acceptance Date October 3, 2024
Published in Issue Year 2024 Volume: 13 Issue: 4

Cite

APA Elmas, A. (2024). Proteogenomic profiling of lung adenocarcinoma reveals therapeutic targets for precision medicine. Niğde Ömer Halisdemir Üniversitesi Mühendislik Bilimleri Dergisi, 13(4), 1545-1552. https://doi.org/10.28948/ngumuh.1542153
AMA Elmas A. Proteogenomic profiling of lung adenocarcinoma reveals therapeutic targets for precision medicine. NOHU J. Eng. Sci. October 2024;13(4):1545-1552. doi:10.28948/ngumuh.1542153
Chicago Elmas, Abdülkadir. “Proteogenomic Profiling of Lung Adenocarcinoma Reveals Therapeutic Targets for Precision Medicine”. Niğde Ömer Halisdemir Üniversitesi Mühendislik Bilimleri Dergisi 13, no. 4 (October 2024): 1545-52. https://doi.org/10.28948/ngumuh.1542153.
EndNote Elmas A (October 1, 2024) Proteogenomic profiling of lung adenocarcinoma reveals therapeutic targets for precision medicine. Niğde Ömer Halisdemir Üniversitesi Mühendislik Bilimleri Dergisi 13 4 1545–1552.
IEEE A. Elmas, “Proteogenomic profiling of lung adenocarcinoma reveals therapeutic targets for precision medicine”, NOHU J. Eng. Sci., vol. 13, no. 4, pp. 1545–1552, 2024, doi: 10.28948/ngumuh.1542153.
ISNAD Elmas, Abdülkadir. “Proteogenomic Profiling of Lung Adenocarcinoma Reveals Therapeutic Targets for Precision Medicine”. Niğde Ömer Halisdemir Üniversitesi Mühendislik Bilimleri Dergisi 13/4 (October 2024), 1545-1552. https://doi.org/10.28948/ngumuh.1542153.
JAMA Elmas A. Proteogenomic profiling of lung adenocarcinoma reveals therapeutic targets for precision medicine. NOHU J. Eng. Sci. 2024;13:1545–1552.
MLA Elmas, Abdülkadir. “Proteogenomic Profiling of Lung Adenocarcinoma Reveals Therapeutic Targets for Precision Medicine”. Niğde Ömer Halisdemir Üniversitesi Mühendislik Bilimleri Dergisi, vol. 13, no. 4, 2024, pp. 1545-52, doi:10.28948/ngumuh.1542153.
Vancouver Elmas A. Proteogenomic profiling of lung adenocarcinoma reveals therapeutic targets for precision medicine. NOHU J. Eng. Sci. 2024;13(4):1545-52.

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