Transcriptomic evidence for tumor‐specific beneficial or adverse effects of TGFβ pathway inhibition on the prognosis of patients with liver cancer
Therapeutic targeting of the transforming growth factor beta (TGFβ) pathway in cancer represents a clinical challenge since TGFβ exhibits either tumor suppressive or tumor promoting properties, depending on the tumor stage. Thus, treatment with galunisertib, a small molecule inhibitor of TGFβ recept...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Wiley
2023-07-01
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| Series: | FEBS Open Bio |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/2211-5463.13647 |
| _version_ | 1797789158920421376 |
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| author | Matthis Desoteux Betty Maillot Kevin Bévant Tanguy Ferlier Raffaële Leroux Gaëlle Angenard Corentin Louis Laurent Sulpice Karim Boudjema Cédric Coulouarn |
| author_facet | Matthis Desoteux Betty Maillot Kevin Bévant Tanguy Ferlier Raffaële Leroux Gaëlle Angenard Corentin Louis Laurent Sulpice Karim Boudjema Cédric Coulouarn |
| author_sort | Matthis Desoteux |
| collection | DOAJ |
| description | Therapeutic targeting of the transforming growth factor beta (TGFβ) pathway in cancer represents a clinical challenge since TGFβ exhibits either tumor suppressive or tumor promoting properties, depending on the tumor stage. Thus, treatment with galunisertib, a small molecule inhibitor of TGFβ receptor type 1, demonstrated clinical benefits only in subsets of patients. Due to the functional duality of TGFβ in cancer, one can hypothesize that inhibiting this pathway could result in beneficial or adverse effects depending on tumor subtypes. Here, we report distinct gene expression signatures in response to galunisertib in PLC/PRF/5 and SNU‐449, two cell lines that recapitulate human hepatocellular carcinoma (HCC) with good and poor prognosis, respectively. More importantly, integrative transcriptomics using independent cohorts of patients with HCC demonstrates that galunisertib‐induced transcriptional reprogramming in SNU‐449 is associated with human HCC with a better clinical outcome (i.e., increased overall survival), while galunisertib‐induced transcriptional reprogramming in PLC/PRF/5 is associated with human HCC with a worse clinical outcome (i.e., reduced overall survival), demonstrating that galunisertib could indeed be beneficial or detrimental depending on HCC subtypes. Collectively, our study highlights the importance of patient selection to demonstrate a clinical benefit of TGFβ pathway inhibition and identifies Serpin Family F Member 2 (SERPINF2) as a putative companion biomarker for galunisertib in HCC. |
| first_indexed | 2024-03-13T01:46:44Z |
| format | Article |
| id | doaj.art-8f3cd7b53e6943a79ed9f68a73604fa1 |
| institution | Directory Open Access Journal |
| issn | 2211-5463 |
| language | English |
| last_indexed | 2024-03-13T01:46:44Z |
| publishDate | 2023-07-01 |
| publisher | Wiley |
| record_format | Article |
| series | FEBS Open Bio |
| spelling | doaj.art-8f3cd7b53e6943a79ed9f68a73604fa12023-07-03T07:24:35ZengWileyFEBS Open Bio2211-54632023-07-011371278129010.1002/2211-5463.13647Transcriptomic evidence for tumor‐specific beneficial or adverse effects of TGFβ pathway inhibition on the prognosis of patients with liver cancerMatthis Desoteux0Betty Maillot1Kevin Bévant2Tanguy Ferlier3Raffaële Leroux4Gaëlle Angenard5Corentin Louis6Laurent Sulpice7Karim Boudjema8Cédric Coulouarn9Inserm, UMR_S 1242, OSS (Oncogenesis Stress Signaling) Centre de Lutte contre le Cancer Eugène Marquis, Univ Rennes FranceDepartment of Hepatobiliary and Digestive Surgery Rennes University Hospital FranceInserm, UMR_S 1242, OSS (Oncogenesis Stress Signaling) Centre de Lutte contre le Cancer Eugène Marquis, Univ Rennes FranceInserm, UMR_S 1242, OSS (Oncogenesis Stress Signaling) Centre de Lutte contre le Cancer Eugène Marquis, Univ Rennes FranceInserm, UMR_S 1242, OSS (Oncogenesis Stress Signaling) Centre de Lutte contre le Cancer Eugène Marquis, Univ Rennes FranceInserm, Inrae, UMR_S 1317 NuMeCan (Nutrition, Metabolisms and Cancer), Univ Rennes FranceInserm, UMR_S 1242, OSS (Oncogenesis Stress Signaling) Centre de Lutte contre le Cancer Eugène Marquis, Univ Rennes FranceInserm, UMR_S 1242, OSS (Oncogenesis Stress Signaling) Centre de Lutte contre le Cancer Eugène Marquis, Univ Rennes FranceDepartment of Hepatobiliary and Digestive Surgery Rennes University Hospital FranceInserm, UMR_S 1242, OSS (Oncogenesis Stress Signaling) Centre de Lutte contre le Cancer Eugène Marquis, Univ Rennes FranceTherapeutic targeting of the transforming growth factor beta (TGFβ) pathway in cancer represents a clinical challenge since TGFβ exhibits either tumor suppressive or tumor promoting properties, depending on the tumor stage. Thus, treatment with galunisertib, a small molecule inhibitor of TGFβ receptor type 1, demonstrated clinical benefits only in subsets of patients. Due to the functional duality of TGFβ in cancer, one can hypothesize that inhibiting this pathway could result in beneficial or adverse effects depending on tumor subtypes. Here, we report distinct gene expression signatures in response to galunisertib in PLC/PRF/5 and SNU‐449, two cell lines that recapitulate human hepatocellular carcinoma (HCC) with good and poor prognosis, respectively. More importantly, integrative transcriptomics using independent cohorts of patients with HCC demonstrates that galunisertib‐induced transcriptional reprogramming in SNU‐449 is associated with human HCC with a better clinical outcome (i.e., increased overall survival), while galunisertib‐induced transcriptional reprogramming in PLC/PRF/5 is associated with human HCC with a worse clinical outcome (i.e., reduced overall survival), demonstrating that galunisertib could indeed be beneficial or detrimental depending on HCC subtypes. Collectively, our study highlights the importance of patient selection to demonstrate a clinical benefit of TGFβ pathway inhibition and identifies Serpin Family F Member 2 (SERPINF2) as a putative companion biomarker for galunisertib in HCC.https://doi.org/10.1002/2211-5463.13647galunisertibgene signaturehepatocellular carcinomasurvivalTGFβ |
| spellingShingle | Matthis Desoteux Betty Maillot Kevin Bévant Tanguy Ferlier Raffaële Leroux Gaëlle Angenard Corentin Louis Laurent Sulpice Karim Boudjema Cédric Coulouarn Transcriptomic evidence for tumor‐specific beneficial or adverse effects of TGFβ pathway inhibition on the prognosis of patients with liver cancer FEBS Open Bio galunisertib gene signature hepatocellular carcinoma survival TGFβ |
| title | Transcriptomic evidence for tumor‐specific beneficial or adverse effects of TGFβ pathway inhibition on the prognosis of patients with liver cancer |
| title_full | Transcriptomic evidence for tumor‐specific beneficial or adverse effects of TGFβ pathway inhibition on the prognosis of patients with liver cancer |
| title_fullStr | Transcriptomic evidence for tumor‐specific beneficial or adverse effects of TGFβ pathway inhibition on the prognosis of patients with liver cancer |
| title_full_unstemmed | Transcriptomic evidence for tumor‐specific beneficial or adverse effects of TGFβ pathway inhibition on the prognosis of patients with liver cancer |
| title_short | Transcriptomic evidence for tumor‐specific beneficial or adverse effects of TGFβ pathway inhibition on the prognosis of patients with liver cancer |
| title_sort | transcriptomic evidence for tumor specific beneficial or adverse effects of tgfβ pathway inhibition on the prognosis of patients with liver cancer |
| topic | galunisertib gene signature hepatocellular carcinoma survival TGFβ |
| url | https://doi.org/10.1002/2211-5463.13647 |
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