PROTEOGENOMIC MARKERS OF CHEMOTHERAPY RESISTANCE AND RESPONSE IN TRIPLE NEGATIVE BREAST CANCER
Microscaled proteogenomics was deployed to probe the molecular basis for differential response to neoadjuvant carboplatin & taxotere combination chemotherapy for triple-negative breast cancer (TNBC). Proteomic analyses of pre-treatment biopsies uniquely revealed that metabolic pathways including oxidative phosphorylation, fatty acid metabolism and glycolysis were resistance-associated. Both proteomics and transcriptomics revealed that sensitivity was marked by elevation of DNA repair, E2F targets, G2M checkpoint, interferon-gamma response, and immune checkpoint components. Proteogenomic analyses of somatic copy number aberrations identified a resistance-associated 19q13.31-33 deletion where LIG1, POLD1 and XRCC1 are located. In orthogonal datasets, LIG1 (DNA ligase I involved in lagging strand synthesis) gene deletion and/or low mRNA expression were associated with lack of pathological complete response and poor prognosis in TNBC, as well as selective carboplatin-resistance in TNBC patient-derived xenograft models. Low expression or LIG1 loss was also associated with higher chromosomal instability index (CIN) and poor prognosis in other cancer types, demonstrating that deletion of lagging- strand synthesis components has broad clinical significance..
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Patent| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Europäisches Patentamt - (2023) vom: 14. Sept. Zur Gesamtaufnahme - year:2023 |
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| Sprache: |
Englisch |
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| Beteiligte Personen: |
ANURAG MEENAKSHI [VerfasserIn] |
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| Links: |
Volltext [kostenfrei] |
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| Themen: |
Sonstige Themen: |
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| Anmerkungen: |
Source: www.epo.org (no modifications made), First posted: 2023-09-14, Last update posted on www.tib.eu: 2023-09-28, Last updated: 2023-09-29 |
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| Patentnummer: |
WO2023172913 |
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| Förderinstitution / Projekttitel: |
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EPA001802240 |
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| 520 | |a Microscaled proteogenomics was deployed to probe the molecular basis for differential response to neoadjuvant carboplatin & taxotere combination chemotherapy for triple-negative breast cancer (TNBC). Proteomic analyses of pre-treatment biopsies uniquely revealed that metabolic pathways including oxidative phosphorylation, fatty acid metabolism and glycolysis were resistance-associated. Both proteomics and transcriptomics revealed that sensitivity was marked by elevation of DNA repair, E2F targets, G2M checkpoint, interferon-gamma response, and immune checkpoint components. Proteogenomic analyses of somatic copy number aberrations identified a resistance-associated 19q13.31-33 deletion where LIG1, POLD1 and XRCC1 are located. In orthogonal datasets, LIG1 (DNA ligase I involved in lagging strand synthesis) gene deletion and/or low mRNA expression were associated with lack of pathological complete response and poor prognosis in TNBC, as well as selective carboplatin-resistance in TNBC patient-derived xenograft models. Low expression or LIG1 loss was also associated with higher chromosomal instability index (CIN) and poor prognosis in other cancer types, demonstrating that deletion of lagging- strand synthesis components has broad clinical significance. | ||
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