# ERK1/2 Signaling in Intrahepatic Cholangiocarcinoma: From Preclinical Advances to Therapeutic Strategies

## TL;DR

This paper reviews how ERK1/2 signaling contributes to aggressive liver cancer and explores new drug strategies to inhibit this pathway for better treatment.

## Contribution

The paper highlights recent preclinical advances in ERK1/2 inhibition as a promising therapeutic strategy for intrahepatic cholangiocarcinoma.

## Key findings

- ERK1/2 hyperactivation is a key driver in intrahepatic cholangiocarcinoma progression.
- Small molecules like PD901, U0126, and Ulixertinib show anti-tumorigenic effects in iCCA.
- ERK1/2 inhibition could be a cornerstone in personalized treatment strategies for iCCA.

## Abstract

Intrahepatic cholangiocarcinoma (iCCA) is a highly aggressive liver cancer with poor prognosis and limited treatment options. Its silent progression is a major hallmark, which delays diagnosis and limits therapeutic success. Extracellular signal-regulated kinase 1/2 (ERK1/2) signaling, which regulates critical cellular functions, is frequently hyperactivated in several types of tumors, including iCCA. Due to its central role in cancer progression, the ERK1/2 cascade has emerged as a promising candidate for target therapy (TT). This review discusses the role of ERK1/2 signaling and highlights recent pre-clinical advances that explore how small molecules can inhibit ERK1/2 pathway hyperactivation. In light of the growing interest in TT and personalized medicine (PM), ERK1/2 signaling emerges as a promising therapeutic target for counteracting iCCA aggressiveness.

Extracellular signal-regulated kinase 1/2 (ERK1/2) is involved in the regulation of the key cellular processes that are essential for the proper functioning of the cell under physiological conditions. Notably, the hyperactivation of ERK1/2 is implicated in oncogenesis and metastatic dissemination across various tumor types, making it an attractive candidate for targeted therapy (TT) through functional inhibition. In intrahepatic cholangiocarcinoma (iCCA), sustained ERK1/2 activation represents one of the major events within the complex signaling network that drives tumor development and progression. In this review, we dissect the biological role of ERK1/2 signaling in iCCA and highlight recent preclinical advances involving selective small-molecule ERK1/2 inhibitors. In vitro and in vivo studies have demonstrated how these inhibitors present effective anti-tumorigenic properties. In particular, PD901 and U0126 effectively reduce iCCA cell proliferation and invasion. Furthermore, Ulixertinib has shown a favorable therapeutic index and encouraging activity in clinical trials involving advanced solid tumors, including iCCA, paving the way for a new therapeutic approach targeting ERK1/2. Nevertheless, the heterogeneous and dynamic molecular landscape of iCCA, often accompanied by drug resistance, presents significant therapeutic challenges. We underscore how targeting the ERK1/2 pathway could represent a cornerstone within a multifaceted therapeutic strategy, fostering the development of personalized treatment approaches and improving clinical outcomes in iCCA patients.