Limitations to the Therapeutic Potential of Tyrosine Kinase Inhibitors and Alternative Therapies for Kidney Cancer

Hossam Kamli,Glenda C Gobe,Li Li

doi:10.31486/toj.18.0015

Abstract

Background: Renal cell carcinomas (RCCs) are the most common primary renal tumor. RCCs have a high rate of metastasis and have the highest mortality rate of all genitourinary cancers. They are often diagnosed late when metastases have developed, and these metastases are difficult to treat successfully. Since 2006, the standard first-line treatment for patients with metastatic RCC has been multitargeted tyrosine kinase inhibitors (TKIs) that include mammalian target of rapamycin (mTOR) inhibitors. RCCs are highly vascularized tumors, and their angiogenesis is controlled by tyrosine kinases that play a vital role in growth factor signaling to stimulate this process. TKI therapy was introduced for direct targeting of angiogenesis in RCC. TKIs have been moderately successful in the treatment of metastatic RCC and initially increased cancer-specific survival times. However, RCC rapidly becomes resistant to TKIs, and no current drug has produced a cure for advanced RCC. Methods: We provide an overview of RCC, explain some reasons for therapy resistance in RCC, and describe some therapies that may overcome resistance to TKIs. The key pathways that determine therapy resistance are illustrated. Results: Factors involved in the development and progression of RCC include genetic mutations, activation of hypoxia-inducible factor and related proteins, cellular metabolism, the tumor microenvironment, and growth factors and their receptors. Resistance to the therapeutic potential of TKIs can be acquired or intrinsic. Alternative therapies include other small molecule drugs and immunotherapy based on immune checkpoint blockade. Conclusion: The treatment of RCC is undergoing a paradigm shift from sole use of small molecule antiangiogenesis TKIs as first-line therapy to include newly approved agents for second-line and third-line therapy that now involve the mTOR pathway and immune checkpoint blockade drugs for patients with advanced RCC.

Highlights

Renal cell carcinomas (RCCs) are the most common kidney neoplasms and the ninth most common malignancy worldwide, representing 2%-4% of all types of cancers.[1]
Since 2006, targeted therapeutics have replaced cytokine therapy and include tyrosine kinase inhibitors (TKIs), mammalian target of rapamycin inhibitors, and angiogenesis/vascular endothelial growth factor (VEGF) inhibitors.[2,3,4,5]. These therapies have been moderately successful in the treatment of metastatic RCC, but a significant problem for patients with RCC is the development of resistance to cancer therapy
We provide an overview of RCC, explain some reasons for therapy resistance in RCC, and describe some therapies that may overcome resistance to TKIs

Summary

Background

RCCs have a high rate of metastasis and have the highest mortality rate of all genitourinary cancers. They are often diagnosed late when metastases have developed, and these metastases are difficult to treat successfully. Since 2006, the standard first-line treatment for patients with metastatic RCC has been multitargeted tyrosine kinase inhibitors (TKIs) that include mammalian target of rapamycin (mTOR) inhibitors. Alternative therapies include other small molecule drugs and immunotherapy based on immune checkpoint blockade.

INTRODUCTION

Findings

CONCLUSION