Strategies to overcome therapeutic resistance in renal cell carcinoma

Abstract

Background: Renal cell cancer (RCC) is a prevalent and lethal disease. At time of diagnosis, most patients present with localized disease. For these patients, the standard of care includes nephrectomy with close monitoring thereafter. While many patients will be cured, 5-year recurrence rates range from 30% to 60%. Furthermore, nearly one-third of patients present with metastatic disease at time of diagnosis. Metastatic disease is rarely curable and typically lethal. Cytotoxic chemotherapy and radiation alone are incapable of controlling the disease. Extensive effort was expended in the development of cytokine therapies but response rates remain low. Newer agents targeting angiogenesis and mTOR signaling emerged in the 2000s and revolutionized patient care. While these agents improve progression free survival, the development of resistance is nearly universal. A new era of immunotherapy is now emerging, led by the checkpoint inhibitors. However, therapeutic resistance remains a complex issue that is likely to persist.

Methods and purpose: In this review, we systematically evaluate preclinical research and clinical trials that address resistance to the primary RCC therapies, including anti-angiogenesis agents, mTOR inhibitors, and immunotherapies. As clear cell RCC is the most common adult kidney cancer and has been the focus of most studies, it will be the focus of this review.

Keywords: Angiogenesis; Immunotherapy; Renal cell carcinoma; Resistance; mTOR.

Figure 1. Mechanisms of anti-angiogenesis resistance

Tumors are capable of continued survival, growth, and proliferation in the setting of persistent VEGFR2 inhibition by several mechanisms including a) activating alternative, compensatory pathways that can continue to support tumor neovascularization and b) reprogramming tumor cells so that they become more invasive, invade deeper into normal tissue, and thus survive using the normal, physiologic vasculature. Ang = angiopoietin, VEGF = vascular epithelial growth factor, VEGFR = vascular epithelial growth factor receptor, TKI = tyrosine kinase inhibitor, HGF = hepatocyte growth factor.

Figure 2. Regulation of the PI3K/AKT/mTOR Pathway

The PI3K/AKT/mTOR pathway is critical to multiple cellular functions and is thus tightly regulated under a) physiologic conditions. However, this pathway becomes dysregulated through a variety of mechanisms in tumors. b) While sometimes an effective anti-tumor maneuver, inhibiting mTORC1 with rapamycin analogs typically leads to resistance through a variety of mechanisms including loss of inhibition of mTORC2, feedback activation of PI3K and AKT, and up-regulation of HIF-2 alpha. RAPA = rapamycin analogs.

Figure 3. Impact of VEGF on Anti-Tumor T Cell Function

Vascular epithelial growth factor (VEGF) produced in the tumor microenvironment has multiple influences on the anti-tumor immune response including a) inhibition of dendritic cell function and enhancing PD-1 expression on T lymphocytes. b) Evidence suggests that VEGFR tyrosine kinase inhibitors (TKIs) may promote some aspects of the anti-tumor immune response by reducing PD-1 expression on lymphocytes, reversing VEGF-induced dendritic cell inhibition, and inhibiting myeloid-derived suppressor cell function. These pro-immune properties of VEGFR TKIs though are balanced by evidence that these drugs can increase PDL-1 expression on tumor cells. Clinical trials are underway to evaluate the combination of VEGFR TKIs and PD-1/PDL-1 check point inhibitors.