An Overview of Renal Cell Carcinoma Hallmarks, Drug Resistance, and Adjuvant Therapies

Abstract

Renal neoplasms are highlighted as one of the 10 most common types of cancer. Renal cell carcinoma (RCC) is the most common type of renal cancer, considered the seventh most common type of cancer in the Western world. The most frequently altered genes described as altered are VHL, PBRM1, SETD2, KDM5C, PTEN, BAP1, mTOR, TP53, TCEB1 (ELOC), SMARCA4, ARID1A, and PIK3CA. RCC therapies can be classified in three groups: monoclonal antibodies, tyrosine kinase inhibitors, and mTOR inhibitors. Besides, there are targeted agents to treat RCC. However, frequently patients present side effects and resistance. Even though many multidrug resistance mechanisms already have been reported to RCC, studies focused on revealing new biomarkers as well as more effective antitumor therapies with no or low side effects are very important. Some studies reported that natural products, such as honey, epigallocatechin-3-gallate (EGCG), curcumin, resveratrol, and englerin A showed antitumor activity against RCC. Moreover, nanoscience is another strategy to improve RCC treatment and reduce the side effects due to the improvement in pharmacokinetics and reduction of toxicities of chemotherapies. Taking this into account, we conducted a systemic review of recent research findings on RCC hallmarks, drug resistance, and adjuvant therapies. In conclusion, a range of studies reported that RCC is characterized by high incidence and increased mortality rates because of the development of resistance to standard therapies. Given the importance of improving RCC treatment and reducing adverse effects, nanoscience and natural products can be included in therapeutic strategies.

Rationale for immune checkpoint inhibitors plus targeted therapy for advanced renal cell carcinoma

“…Sunitinib, pazopanib, and bevacizumab are anti-VEGF drugs that result in endothelial cell injury and podocyte lesions due to their antiangiogenic effect, and they subsequently cause proteinuria, hypertension and other renal injuries [ 118 ]. It also affects the turnover of endothelial cells during trauma, leading to hypercoagulability and thromboembolism [ 119 ]. For example, bevacizumab can directly beget cells and induce thrombotic microangiopathy (TMA) [ 120 ].…”

Teaching an Old Drug a New Trick: Targeting Treatment Resistance in Genitourinary Cancers

“…The majority of kidney tumors are RCC, among which clear cell RCC is the major histologic subtype while papillary, chromophobe, and tumor in the collecting duct are remaining subtypes; some of the tumors can have a sarcomatoid variant [ 23 ]. While the standard treatment for clinically localized RCC is nephrectomy with lymph node dissection, about 1/4 th of the newly diagnosed patients have metastatic disease and about 1/4 th more develop metastatic disease following radical nephrectomy requiring a systemic treatment approach [ 24 , 25 ]. The prognosis for patients with metastatic renal cell carcinoma (mRCC) remains poor.…”

“…The survival of patients with mRCC is about 20% survival at two years and less than 10% at five years. Unlike other solid tumors and hematological cancers, RCC is not amenable to chemotherapy or radiation therapy due to treatment resistance [ 24 , 26 ]. Awakening an immunological response with generalized cytokine immune therapy (i.e., interferon-alpha, and interleukin-2 treatment) was a first-line treatment for mRCC up until the mid-2000s.…”

“…Anti-angiogenic therapy improved the progression-free survival rates with lesser toxicities than the generalized cytokine immune therapy leading to the approval of tyrosine kinase inhibitors (TKIs) such as Sorafenib, Sunitinib, pazopanib, and cabozantinib, axitinib, mTOR inhibitors such as temsirolimus and everolimus and an anti-VEGF monoclonal antibody (bevacizumab) for the treatment of mRCC [ 3 , 24 , 28 ]. Immunotherapy has been approved for mRCC since 2015.…”

“…However, despite the approval of several TKIs, mTOR inhibitors, an anti-VEGF antibody and immunotherapy, mRCC still poses a grim prognosis for patients with dismal overall and relapse-free survival. The challenges for these treatments are therapy resistance and treatment-related side effects [ 3 , 24 ]. A rarely explored avenue to overcome treatment failure is to target the mechanism by which a specific drug is inactivated in tumors.…”