Metastatic renal cell carcinoma (mRCC) remains one of the most challenging cancers to treat, with an overall survival rate below 10% at five years from diagnosis. Approximately 30% of RCC patients present with metastatic disease at the time of diagnosis, and disease recurrence occurs in about 30% of patients after surgical treatment. Clear cell renal cell carcinoma (ccRCC) accounts for roughly 70% of all kidney cancers, with papillary and chromophobe subtypes being less common.
First-line treatment for mRCC currently relies on antiangiogenic drugs that inhibit tyrosine kinase receptors (TKIs) combined with immuno-oncology therapies or immune checkpoint inhibitor combinations. Second-line therapy involves additional TKIs, immunotherapeutic drugs, and mTOR inhibitors. However, many patients develop primary or acquired drug resistance, rendering these therapies ineffective over time.
The investigation of molecular mechanisms underlying RCC, particularly in ccRCC, has revealed multiple dysregulated signaling pathways that present opportunities for novel therapeutic targeting. These include the VHL-HIF-VEGFR-mTOR axis, RTK-PI3K-Akt signaling, p53-related pathways, autophagy, and ferroptosis, each offering distinct avenues for drug development.
RCC is classified into three main histotypes: clear cell (ccRCC, ~70%), papillary (pRCC with type 1 and type 2 subtypes), and chromophobe (chRCC). Tumor staging follows the TNM classification system across four stages, which directly determines treatment strategy. Stages I through III generally involve surgical approaches including partial or radical nephrectomy, while Stage IV may require cytoreductive nephrectomy before systemic therapy.
Radical nephrectomy (RN) remains the standard treatment for localized renal masses not suitable for nephron-sparing surgery. The robotic-assisted approach has rapidly become the most common surgical method, with utilization increasing from 1.5% in 2003 to 27% in 2015. Robotic partial nephrectomy has shown superior outcomes compared to laparoscopic and open approaches in terms of blood loss, transfusions, complications, and hospital stay.
For post-surgical management, metastatic RCC patients are risk-stratified into favorable, intermediate, and poor-risk categories. Current guidelines recommend combination therapies such as pembrolizumab/axitinib or nivolumab/cabozantinib depending on risk group, reflecting a shift toward immunotherapy-based regimens as the standard of care.
The VHL-HIF-VEGFR-mTOR axis is the most well-characterized pathway in ccRCC. VHL loss of function, a common event in ccRCC, prevents the ubiquitination and degradation of hypoxia-inducible factors (HIFs), leading to VEGF expression and promoting angiogenesis and tumor growth. VHL dysfunction also causes mTOR hyperactivation, which correlates with tumor progression and poor patient outcomes.
The RTK-PI3K-Akt pathway is driven by the accumulation of HIF, which increases VEGFR expression. Multiple tyrosine kinases including PDGFR, Axl, and MET are also involved in ccRCC biology. The binding of VEGFR and PDGFR with their ligands activates PI3K, enhancing AKT kinase activity which in turn stimulates tumor progression and inactivates pro-apoptotic proteins. MET dysregulation is particularly notable for promoting resistance to targeted therapies.
Additional critical pathways include p53-related signaling, where the tumor suppressor is often suppressed through proteasome degradation or autophagy rather than direct mutation, and ferroptosis, a newly recognized form of iron-dependent oxidative cell death regulated by the Hippo-YAP/TAZ pathway that represents a novel therapeutic avenue.
First-generation TKIs such as sunitinib, sorafenib, and pazopanib are being replaced by more efficient agents due to primary and acquired resistance. Cabozantinib, an inhibitor of VEGFR, MET, and Axl, has demonstrated increased progression-free survival (PFS) compared to sunitinib. Axitinib has shown greater objective response rates and improved median PFS compared to sorafenib in clinical trials.
Lenvatinib, a multitarget kinase inhibitor affecting VEGFR, FGFR, PDGFR, RET, and KIT, has demonstrated antitumor properties against mRCC. Tivozanib, a selective VEGFR inhibitor approved by the European Medicines Agency, showed PFS advantage over sorafenib though overall survival results favored sorafenib. Current guidelines now recommend combining these TKIs with PD-1 immune checkpoint inhibitors for first-line treatment.
The combination of newer TKIs with immune checkpoint inhibitors in first-line settings has shown superior efficacy compared to single-drug therapies. This combination approach represents a paradigm shift from the previous monotherapy strategy of using TKIs alone to inhibit angiogenesis, and forms the current standard of care for patients with advanced RCC across all risk groups.
HIF pathway targeting shows promise for metastatic ccRCC treatment. The HIF2 antagonist PT2399 demonstrated greater activity than sunitinib and was well tolerated in mouse models, though prolonged treatment leads to resistance. A second antagonist, PT2385, inhibits both HIF2 binding and HIF-2-related gene expression and was safe in a first-in-human phase I trial, though follow-up data on PFS and overall survival remain pending.
Belzutifan, an oral HIF2 inhibitor, has shown particularly encouraging results. In a phase-II clinical trial for patients with VHL disease-associated renal carcinomas, about 49% of patients achieved an objective response, with only 3% experiencing progressive disease. The drug was well tolerated with anemia as the main side effect, making it an important emerging option for mRCC treatment.
PI3K-related inhibitors have shown more modest results. MK-2206, an AKT inhibitor, did not demonstrate significant differences compared to everolimus. Dual PI3K and mTOR inhibitors like BEZ235 and apitolisib showed high toxicity without objective improvements. The limited efficacy may be explained by extensive crosstalk and negative feedback mechanisms in PI3K-related pathways.
Since p53 can be removed by MDM2-proteasome machinery in kidney tumor cells, targeting this system represents a therapeutic strategy for ccRCC. The inhibition of MDM2 reduced tumor size in pre-clinical models, and combined MDM2 inhibitor and everolimus treatment showed synergistic effects in decreasing cell growth. Several MDM2 inhibitors including RG7112, idasanutlin, APG-115, and ALRN-6924 have completed phase-1 trials with generally acceptable tolerability.
Proteasome inhibitors offer another approach to preserve wild-type p53 and arrest tumor growth. Bortezomib can induce apoptosis in RCC cell lines, though a phase-II study testing sorafenib plus bortezomib did not improve PFS over sorafenib alone. Carfilzomib showed antitumoral activity in preclinical models but failed in a phase-II mRCC trial where all enrolled patients experienced disease progression.
These observations collectively suggest that while MDM2 inhibitors hold promise in pre-clinical settings and early-phase trials, proteasome inhibitors appear unsuitable for treating metastatic renal carcinoma. The challenge remains translating the p53-restoration strategy from laboratory findings into clinically effective therapies for kidney cancer patients.
Autophagy plays a dual role in mRCC, contributing to drug resistance by sequestering therapeutic agents in lysosomal vesicles and removing the tumor suppressor p53 through the autophagic system. Clinical trials combining the autophagy inhibitor hydroxychloroquine (HCQ) with everolimus showed better PFS compared to everolimus alone in patients previously treated with TKIs, with generally acceptable tolerability.
The enzyme transglutaminase 2 (TG2) connects p53 with the autophagic protein SQSTM1/p62, facilitating p53 sequestration into autophagosomes. Autophagy-related drug resistance appears to be mediated by TG2, making its inhibition a potential strategy to improve cancer therapy. Treatment with streptonigrin, a TG2 inhibitor, reduced cancer cell growth in xenograft models of RCC.
These findings highlight that targeting autophagy and TG2 could address the critical problem of drug resistance in mRCC. By disrupting the autophagic machinery that degrades both therapeutic agents and tumor suppressors, these approaches may re-sensitize cancer cells to conventional therapies and restore p53 function simultaneously.
Ferroptosis induction by erastin and sorafenib can inhibit tumor progression and restore therapeutic effectiveness in RCC. Artesunate (ART), a traditional Chinese medicine drug, has shown anticancer properties by increasing ROS species and inhibiting GPX4 to cause ferroptosis, though its mechanism varies across different RCC cell lines. Combining erastin and RSL-3 with everolimus inhibits RCC cell viability and may overcome drug resistance observed after everolimus treatment.
Immunotherapy has become central to mRCC treatment, with immune checkpoint inhibitors (ICIs) including nivolumab, ipilimumab, pembrolizumab, and avelumab now in clinical use. The combination of nivolumab (anti-PD-1) and ipilimumab (anti-CTLA4) is the standard of care for intermediate and poor-risk mRCC patients. Pembrolizumab has also been shown to prolong disease-free survival in high-risk patients after nephrectomy.
Despite these advances, long-term ICI-based therapies may induce resistance mechanisms that decrease clinical benefits. Innovative approaches including modified cytokines, cellular therapies, and anticancer vaccines are being explored. The development of predictive biomarkers for therapeutic response in ICI-treated patients remains a critical unmet need.
The therapeutic landscape for mRCC is rapidly evolving, with TKIs combined with immune checkpoint inhibitors now established as first-line treatment across all risk groups. Immuno-oncology therapies are also recommended for intermediate and poor-risk groups. Among emerging agents, the HIF2 inhibitor belzutifan stands out as particularly promising, showing improved PFS compared to conventional therapies when used alone or in combination.
Autophagy inhibitors such as hydroxychloroquine in combination with everolimus have demonstrated superior PFS compared to single-agent treatment. MDM2 inhibitors, TG2 inhibitors, and ferroptosis activators show ability to inhibit tumor cell growth in pre-clinical models, though clinical validation studies are still needed. Conversely, Akt, PI3K, and proteasome inhibitors have not demonstrated sufficient efficacy and carry significant side effects.
The research and validation of new targeting drugs combined with the physiopathological features of kidney cancer could ultimately lead to personalized medicine approaches. Treatment using autophagy inhibitors and ferroptosis activators may limit drug resistance effects by re-sensitizing cancer cells to conventional therapy, representing a key strategy for improving outcomes in mRCC patients.