Targeting CRAF kinase in anti-cancer therapy: progress and opportunities

Abstract

The RAS/mitogen-activated protein kinase (MAPK) signaling cascade is commonly dysregulated in human malignancies by processes driven by RAS or RAF oncogenes. Among the members of the RAF kinase family, CRAF plays an important role in the RAS-MAPK signaling pathway, as well as in the progression of cancer. Recent research has provided evidence implicating the role of CRAF in the physiological regulation and the resistance to BRAF inhibitors through MAPK-dependent and MAPK-independent mechanisms. Nevertheless, the effectiveness of solely targeting CRAF kinase activity remains controversial. Moreover, the kinase-independent function of CRAF may be essential for lung cancers with KRAS mutations. It is imperative to develop strategies to enhance efficacy and minimize toxicity in tumors driven by RAS or RAF oncogenes. The review investigates CRAF alterations observed in cancers and unravels the distinct roles of CRAF in cancers propelled by diverse oncogenes. This review also seeks to summarize CRAF-interacting proteins and delineate CRAF's regulation across various cancer hallmarks. Additionally, we discuss recent advances in pan-RAF inhibitors and their combination with other therapeutic approaches to improve treatment outcomes and minimize adverse effects in patients with RAF/RAS-mutant tumors. By providing a comprehensive understanding of the multifaceted role of CRAF in cancers and highlighting the latest developments in RAF inhibitor therapies, we endeavor to identify synergistic targets and elucidate resistance pathways, setting the stage for more robust and safer combination strategies for cancer treatment.

Resistance patterns in drug-adapted cancer cell lines reflect complex evolution in clinical tumors

“…GXYLT1 , KRTAP4-11 , and RGPD4 were the genes among those had not previously been associated with drug resistance that displayed de novo mutations in the most (7) resistant sublines (Fig.3A, SupFile.4). GXYLT1 promotes metastasis formation in colorectal cancer through MAPK signaling, a pathway known to provide resistance to a range of anti-cancer drugs 35–38 . RGPD4 was correlated with vascular invasion in HBV-associated hepatocellular carcinoma, and it is known that there is an overlap between pro-angiogenic, pro-metastatic, and resistance-associated signaling in cancer 36,39 .…”

“…3A, SupFile.4). GXYLT1 promotes metastasis formation in colorectal cancer through MAPK signaling, a pathway known to provide resistance to a range of anti-cancer drugs [35][36][37][38] . RGPD4 was correlated with vascular invasion in HBV-associated hepatocellular carcinoma, and it is known that there is an overlap between pro-angiogenic, pro-metastatic, and resistanceassociated signaling in cancer 36,39 .…”