Abbisko Therapeutics has published breakthrough preclinical translational research of FGFR4 inhibitors in “Molecular Cancer Therapeutics”, an internationally renowned journal published by the American Association for Cancer Research (AACR). The recently online article comprehensively elucidated major resistance mechanisms of the FGFR4 inhibitors, and for the first time discovered that EGFR activation is a primary factor leading to resistance to FGFR4 inhibitors in HCC. It further revealed the strong potential of combinational therapies of EGFR and FGFR4 inhibitors and a new direction for the future clinical development of FGFR4 inhibitors. 

According to statistics from the International Agency for Research on Cancer (IARC) of the World Health Organization (WHO), primary liver cancer ranks sixth in terms of the malignant tumor incidence rate worldwide in 2020, with 906,000 new cases and 830,000 deaths per year. Hepatocellular carcinoma (HCC), as the most common type of liver cancer, accounts for 85% to 90% of primary liver cancers. HCC is highly malignant, and the existing treatment methods still cannot satisfy the long-term survival benefits. For the treatment of HCC, there are still huge unmet clinical needs.

Aberrant activation of the FGF19-FGFR4 signaling pathway has been reported to play an essential role in the tumorigenesis of HCC. FGFR4 inhibitors have emerged as novel therapies for the treatment of HCC. Several FGFR4 inhibitors, includingirpagratinib (ABSK011) discovered and developed by Abbisko, have advanced into clinical studies and demonstrated preliminary efficacy. However, FGFR4 inhibitors such as Blu-554 have shown suboptimal clinical responsive rates and durations of response in clinical trials, which are highly likely caused by various resistance mechanisms.

To elucidate the potential resistant mechanisms, Abbisko developed a set of cellular models with resistance to FGFR4 inhibitors. By utilizing these models, we discovered that the activation of EGFR MAPK/AKT signaling is a primary mechanism mediating the acquired resistance to FGFR4 inhibitors. Further research revealed that EGFR activation also plays a crucial role in intrinsic resistance. By combining with EGFR or SHP2 inhibitors, FGFR4 inhibitors have shown excellent efficacy in these acquired resistance and other HCC models.  

Compensating activation of bypass pathways is one of the most common mechanisms rendering resistance to TKIs. In this study, Abbisko for the first time demonstrated that EGFR activation could lead to resistance to specific FGFR4 inhibition in HCC, confirming the strong correlation between EGFR and FGFR their reciprocal resistance as reported in many literature studies. In 2021, researchers from Renji Hospital also published a relevant paper in "Nature", which reported that EGFR contributed to resistance to lenvatinib, and lenvatinib synergizes with EGFR inhibitors mainly through modulation of FGFR1-3 signaling.

Reference：

1. Bin Shen, Jueping Shi, Zhixuan Zhu, Zhui Chen, Nannan Zhang, et al. EGFR inhibition overcomes resistance to FGFR4 inhibition and potentiates FGFR4 inhibitor therapy in hepatocellular carcinoma. Mol Cancer Ther 2023.

2. Jin H, Shi Y, Lv Y, Yuan S, Ramirez CFA, Lieftink C, et al. EGFR activation limits the response of liver cancer to lenvatinib. Nature 2021;595:730-4.