Transcriptomic evidence for tumor‐specific beneficial or adverse effects of TGFβ pathway inhibition on the prognosis of patients with liver cancer

Abstract

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.

Unraveling breast cancer prognosis: a novel model based on coagulation-related genes

“…This hints at a potential tumor-suppressive function of SERPINA1 in breast cancer, whereby its diminished expression may facilitate tumor progression and metastasis ( Chan et al, 2015 ; Zhao et al, 2018 ). Belonging to the same family as SERPINA1, SERPINF2 specifically enriches in hepatocytes ( Hou, 2022 ; Desoteux et al, 2023 ). Previous studies have indicated a correlation between SERPINF2 with unfavorable outcomes in advanced serous ovarian cancer, and laboratory tests have confirmed its crucial involvement in tumor growth and spread ( Huh et al, 2022 ).…”

Unlocking the Potential of Therapy-Induced Cytokine Responses: Illuminating New Pathways in Cancer Precision Medicine

“…In malignant cells, cancer therapy using drugs or radiation elicits ‘danger’ signaling pathways, which have, primarily, a protective nature. These signals could be mediated by cytokines, and some cytokine pathways, such as transforming growth factor-beta (TGF-β), may have dual roles of inhibition or acceleration of tumor growth [ 41 , 42 ]. Other cytokine pathways may drive cell death, attract or deflect immune cells, or induce a senescence-like state to remain dormant through the stress period [ 43 , 44 , 45 , 46 ].…”