Dataset Information
Ribociclib enhances infigratinib-induced cancer cell differentiation and delays resistance in FGFR-driven hepatocellular carcinoma.
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ABSTRACT: Background & aims
Infigratinib is a pan-FGFR (fibroblast growth factor receptor) inhibitor that has shown encouraging activity in FGFR-dependent hepatocellular carcinoma (HCC) models. However, long-term treatment results in the emergence of resistant colonies. We sought to understand the mechanisms behind infigratinib-induced tumour cell differentiation and resistance and to explore the potential of adding the CDK4/6 inhibitor ribociclib to prolong cell differentiation.Methods
Nine high and three low FGFR1-3-expressing HCC patient-derived xenograft (PDX) tumours were subcutaneously implanted into SCID mice and subsequently treated with either infigratinib alone or in combination with ribociclib. Tumour tissues were then subjected to immunohistochemistry to assess cell differentiation, as indicated by the cytoplasmic-to-nuclear ratio and markers such as CYP3A4, HNF4? and albumin. Western blot analyses were performed to investigate the signalling pathways involved.Results
Infigratinib induced cell differentiation in FGFR1-3-dependent HCC PDX models, as indicated by an increase in the cytoplasmic/nuclear ratio and an increase in CYP3A4, HNF4? and albumin. Resistant colonies emerged in long-term treatment, characterised by a reversal of differentiated cell morphology, a reduction in the cytoplasmic-to-nuclear ratio and a loss of differentiation markers. Western blot analyses identified an increase in the CDK4/Cdc2/Rb pathway. The addition of ribociclib effectively blocked this pathway and reversed resistance to infigratinib, resulting in prolonged cell differentiation and growth inhibition.Conclusions
Our findings demonstrate that the combined inhibition of FGFR/CDK4/6 pathways is highly effective in providing long-lasting tumour growth inhibition and cell differentiation and reducing drug resistance. Therefore, further clinical investigations in patients with FGFR1-3-dependant HCC are warranted.
SUBMITTER: Prawira A
PROVIDER: S-EPMC7894323 | biostudies-literature | 2021 Mar
REPOSITORIES: biostudies-literature
Publications
Ribociclib enhances infigratinib-induced cancer cell differentiation and delays resistance in FGFR-driven hepatocellular carcinoma.
Liver international : official journal of the International Association for the Study of the Liver 20201123 3
<h4>Background & aims</h4>Infigratinib is a pan-FGFR (fibroblast growth factor receptor) inhibitor that has shown encouraging activity in FGFR-dependent hepatocellular carcinoma (HCC) models. However, long-term treatment results in the emergence of resistant colonies. We sought to understand the mechanisms behind infigratinib-induced tumour cell differentiation and resistance and to explore the potential of adding the CDK4/6 inhibitor ribociclib to prolong cell differentiation.<h4>Methods</h4>Ni ...[more]