Ribociclib enhances infigratinib-induced cancer cell differentiation and delays resistance in FGFR-driven hepatocellular carcinoma

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 alpha 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 alpha 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.

Automated summary

Infigratinib has shown promising activity in FGFR-dependent HCC models, but long-term treatment can lead to the development of drug-resistant colonies. This study explored the mechanisms behind infigratinib-induced tumor cell differentiation and resistance, as well as the potential of combining it with the CDK4/6 inhibitor ribociclib to prolong cell differentiation. The combination of FGFR and CDK4/6 pathway inhibition proved to effectively inhibit tumor growth, promote cell differentiation, and reduce drug resistance in HCC. Further clinical investigations in patients with FGFR1-3-dependent HCC are recommended.