Renal cancer: signaling pathways and advances in targeted therapies

Abstract

Renal cancer is a highlyheterogeneous malignancy characterized by rising global incidence and mortalityrates. The complex interplay and dysregulation of multiple signaling pathways,including von Hippel-Lindau (VHL)/hypoxia-inducible factor (HIF), phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR), Hippo-yes-associated protein (YAP), Wnt/ß-catenin, cyclic adenosine monophosphate (cAMP), and hepatocyte growth factor (HGF)/c-Met, contribute to theinitiation and progression of renal cancer. Although surgical resection is thestandard treatment for localized renal cancer, recurrence and metastasiscontinue to pose significant challenges. Advanced renal cancer is associatedwith a poor prognosis, and current therapies, such as targeted agents andimmunotherapies, have limitations. This review presents a comprehensiveoverview of the molecular mechanisms underlying aberrant signaling pathways inrenal cancer, emphasizing their intricate crosstalk and synergisticinteractions. We discuss recent advancements in targeted therapies, includingtyrosine kinase inhibitors, and immunotherapies, such as checkpoint inhibitors.Moreover, we underscore the importance of multiomics approaches and networkanalysis in elucidating the complex regulatory networks governing renal cancerpathogenesis. By integrating cutting-edge research and clinical insights, this review contributesto the development of innovative diagnostic and therapeutic strategies, whichhave the potential to improve risk stratification, precision medicine, andultimately, patient outcomes in renal cancer.

Keywords: molecular mechanisms; precision medicine; renal cancer; signaling pathways; targeted therapy.

FIGURE 1

Schematic representation of the critical signaling pathways implicated in the pathogenesis and targeted therapy of RCC. The intricate crosstalk among diverse signaling cascades, including VHL/HIF, PI3K/AKT/mTOR, Hippo–YAP, Wnt/β‐catenin, cAMP, HGF/c‐Met, p53, ferroptosis‐related, cuproptosis‐related, NF‐κB, and TGF‐β pathways, plays a pivotal role in the malignant progression of RCC. Elucidating the molecular mechanisms governing these pathways is paramount for devising novel therapeutic strategies and enhancing patient prognosis. This figure was created based on the tools provided by Biorender.com.

FIGURE 2

The VHL–HIF–VEGFR–mTOR signaling pathway in the pathogenesis of renal cancer. Under normoxic conditions, the von Hippel–Lindau (VHL) protein (pVHL) recognizes and ubiquitinates hypoxia‐inducible factor‐α (HIF‐α), targeting it for degradation by the 26S proteasome. In renal cancer, inactivating mutations or deletions of the VHL gene lead to the accumulation of HIF‐α, which subsequently dimerizes with HIF‐β and translocates to the nucleus. The HIF heterodimer binds to hypoxia response elements (HREs) in the promoter regions of target genes, including vascular endothelial growth factor (VEGF), platelet‐derived growth factor (PDGF), and carbonic anhydrase IX (CAIX), thereby activating their transcription and promoting tumor angiogenesis, proliferation, and metastasis. VEGF stimulates the proliferation of vascular endothelial cells and mediates cancer stem cell self‐renewal via the VEGF receptor 2 (VEGFR‐2)/Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) signaling axis. Furthermore, HIF‐1α activates the expression of Twist‐related protein 1 (TWIST1) and regulates the Snail/Slug/zinc finger E‐box‐binding homeobox 1 (ZEB1) axis, inducing epithelial–mesenchymal transition (EMT) and enhancing the invasive and metastatic potential of tumor cells. The secretion of inflammatory factors, such as transforming growth factor‐β (TGF‐β), further exacerbates the EMT process and tumor progression. Moreover, VHL inactivation leads to the hyperactivation of mammalian target of rapamycin (mTOR), which is associated with tumor progression and worse prognosis in renal cancer. This figure was created based on the tools provided by Biorender.com.

FIGURE 3

The therapeutic strategies in renal cancer. (A) Major surgical treatment options and SBRT for renal cancer. OPN, open partial nephrectomy; ORN, open radical nephrectomy; RAPN, robot‐assisted partial nephrectomy; RARN, robot‐assisted radical nephrectomy; LPN, laparoscopic partial nephrectomy; LRN, laparoscopic radical nephrectomy. (B) Cytokine therapy options for renal cancer, including IL‐2, TNF‐α, and IFN‐α. (C) Targeted therapy options for renal cancer, including TKIs and mTOR inhibitors. (D) Immune checkpoint inhibitor options for renal cancer, including anti‐PD‐1, anti‐PD‐L1, anti‐LAG3, and anti‐CTLA4. (E) Novel immunotherapy options for renal cancer, including DC vaccines, ADC, and CAR‐T. (F) Novel targeted therapy options for renal cancer, including HIF inhibitors and CDK4/6 inhibitors. This figure was created based on the tools provided by Biorender.com.

FIGURE 4

Timeline illustrating the evolving treatment landscapes and research history of renal cancer. This timeline describes the development of systemic therapies for renal cancer, exemplifying representative agents from the cytokine therapy era, the targeted therapy era, and the immunotherapy era, as well as reflections on possible future directions. This figure was created based on the tools provided by Biorender.com.

FIGURE 5

Future directions in RCC research: unraveling molecular mechanisms, devising innovative diagnostic and therapeutic approaches, exploring drug resistance and inflammation‐associated pathways, and promoting adoptive cell therapy to optimize patient outcomes. This figure was created based on the tools provided by Biorender.com.