![]() The morbidity and mortality rates of advanced RCC are high, with a five-year survival rate of only 18%. These patient groups are considered at high risk of death due to RCC. Around 50% of RCC is detected incidentally with one-quarter of the patients diagnosed with metastatic disease and another 30% that relapse and develop metastatic RCC (mRCC) after undergoing curative nephrectomy. Papillary RCC (10–15%) and chromophobe RCC (5%) are the common remaining histologic subtypes. According to the 2012 consensus conference of the International Society of Urological Pathology (ISUP), there are 15 subtypes of RCC with diverse genetic and epigenetic characteristics, of which clear cell RCC (ccRCC) occurs most frequently (80%). RCC arises from the renal tubular epithelium, which lines the proximal convoluted tubules and constitutes of very small tubes in the kidney responsible for transporting urine. Renal cell carcinoma (RCC) makes up to 95% of renal malignancies. In 2018, there were 400,000 new cases around the globe. Kidney cancer is the ninth most common cancer in men and fourteenth in women. In this article, we review recent findings on the emerging understanding of RCC pathology, VEGF-TKI and ICI resistance mechanisms, and potential avenues to overcome these resistance mechanisms through rationally designed combination therapies. Hence, an understanding of the mechanisms of VEGF-TKI and ICI resistance will help in formulating useful knowledge about developing effective treatment strategies for patients with advanced RCC. Although some patients exhibit potent responses, a non-negligible number of patients are innately resistant or develop resistance within a few months to ICI therapy. Further, in the last 5 years, immune checkpoint inhibitors (ICIs) have revolutionized RCC treatment. However, recent studies have shown the restoration of an alternative angiogenesis pathway in modulating resistance. ![]() One of the mechanisms of VEGF-TKIs is inhibition of the classical angiogenesis pathway. In the past decade, several molecular and genetic mechanisms of VEGF-TKI resistance have been reported. ![]() Despite its early promising results in decreasing or delaying the progression of RCC in patients, VEGF-TKIs have provided modest benefits in terms of disease-free progression, as 70% of the patients who initially respond to the treatment later develop drug resistance, with 30% of the patients innately resistant to VEGF-TKIs. Vascular endothelial growth factor tyrosine kinase inhibitors (VEGF-TKIs) have been the mainstay of treatment for patients with advanced renal cell carcinoma (RCC). ![]()
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