Tyrosine Kinases and the Treatment of Renal Cell Carcinomas

The effectiveness of emerging cancer therapies such as tyrosine kinase inhibitors (TKIs) depends greatly on an understanding of cancer genetics and cancer cell biology. Tyrosine kinases are an essential component of cellular signal transduction pathways that transmit external chemical signals to the nucleus. Mutations in the genes coding for tyrosine kinases are consequently associated with a loss of regulation of cell division and apoptosis, potentially leading to cancer.1 Understanding this, and developing therapeutic medicines that specifically target tyrosine kinases has been a revolutionary step forward in the treatment of renal cell carcinoma. Dr Andrew Dean, Medical Oncologist, Palliative Care Consultant and Medical Director of Virtual Medical Centre, says that before TKIs became available, treatment options for RCC were far from satisfactory. “Tyrosine kinase inhibitors were the first class of drugs that were effective and had tolerable side-effects,” said Dr Dean. This article will examine the role of tyrosine kinases in normal cellular function, the effects of genetic mutations leading to unregulated tyrosine kinase activity and the role of tyrosine kinase inhibitors in modern cancer treatments.

Functions of Tyrosine Kinases

To transmit extracellular molecular signals and modulate the activity of transcription factors, cells use complex signal transduction pathways activated by cell membrane receptors.¹ These pathways employ cascades of sequentially activated proteins and lipids, usually requiring phosphorylation of target proteins via adenosine triphosphate (ATP). Addition or removal of phosphate groups is performed by kinase enzymes, such as tyrosine kinases. Tyrosine kinases are classified into two major sub-groups: Receptor tyrosine kinases and non-receptor tyrosine kinases.²

Receptor tyrosine kinases are trans-membrane proteins with an extracellular domain for the binding of ligands and a catalytic intracellular kinase domain for signal transmission.² When ligands bind to the receptor, auto-phosphorylation of the cytoplasmic domain occurs and tyrosine kinase becomes activated, permitting movement of the extracellular signal into a variety of intracellular signalling cascades. Conversely, non-receptor tyrosine kinases do not have an extracellular component and are found in the cytosol. They are recruited by a diverse range of intracellular signalling pathways and are critical to signal transduction to the nucleus.²

Signal transduction pathways mediated by tyrosine kinases can cause a variety of intra-nuclear changes, such as up- or down-regulation of protein transcription, cell growth, division, differentiation, migration or apoptosis.³ Common receptors such as vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR) and colony-stimulating factor-1 receptor all have tyrosine kinase domains.³

Tyrosine Kinase Dysfunction

Tyrosine kinases, like other proteins, are susceptible to the effects of genetic changes such as mutations, chromosomal translocations or amplification. This can alter their structure and function, causing signal transduction pathways to become dysregulated. Consequently, cellular proliferation, migration and survival can become disordered and/or unresponsive to other cellular regulation modalities.¹ Tyrosine kinase dysfunction is associated with a wide range of human cancers, such as breast, ovary, lung, stomach, colon, cervix, kidney, haematological, prostate, thyroid and liver cancer.¹²

There are a few mechanisms whereby the function of tyrosine kinases are altered.¹ This can occur due to changes within the structure of a tyrosine kinase itself or within an associated receptor domain, altering the activity of the otherwise normal tyrosine kinase domain.² Abnormal fusion with a partner protein can cause constitutive activation of both receptor and non-receptor tyrosine kinases in the absence of ligand stimulation. This is the pathogenesis of the well-known BCR-ABL fusion tyrosine kinase in chronic myeloid leukaemia. Mutations in the receptor component of tyrosine kinases can also cause constitutive activation or increased receptor sensitivity to ligand binding. Tyrosine phosphatases are enzymes responsible for removing phosphate groups from tyrosine kinases to down-regulate their activity. A lack of tyrosine phosphatase activity or a decreased expression of tyrosine kinase inhibitor proteins can also result in increased tyrosine kinase activity.² These disease pathways are seen in many human cancers where cell survival, proliferation and resistance to cytotoxic drugs are increased. Tyrosine kinases are therefore an important target for novel anti-cancer therapeutics. Tyrosine kinase inhibitors are now in use against many cancers, such as patients with advanced or stage IV renal cell carcinoma.⁴ 

The EGFR family of tyrosine kinases have been the most extensively investigated. Overexpression or dysregulation of EGFR-associated tyrosine kinases are correlated with a poorer prognosis in ovarian, head and neck, oesophageal, cervical, bladder, breast, colorectal, gastric, and endometrial cancers.¹²

Cancer treatments targeting Tyrosine Kinase

Tyrosine kinase inhibitors are designed to restrict the catalytic activity of tyrosine kinases either by obstructing function of the kinase enzymatic domain or obstructing stimulation of the receptor domain by relevant ligands.³ The first natural tyrosine kinase inhibitors were developed in the 1980’s. Since then, development of natural or synthetic compounds inhibiting tyrosine kinase-mediated pathways has exploded and hundreds of clinical trials are currently ongoing.¹²

Some antibody therapies (such as bevacizumab) use antibody-mediated cytotoxicity of cells expressing aberrant forms of tyrosine kinases. Multiple receptor tyrosine kinase (rtk) inhibitors such as imatinib (Glivec), sunitinib (Sutent), sorafenib (Nexavar), pazopanib (Votrient), erlotinib (Tarceva), and gefitinib (Iressa)¹⁰ have a defined place as cancer treatments are being investigated in multiple tumour streams.¹¹

The prime example of the use of tyrosine kinase inhibitor therapy in human cancers is the use of imatinib for the treatment of chronic myeloid leukaemia (CML).² 95% of patients with CML have a characteristic chromosomal 9:22 translocation known as the Philadelphia chromosome. This translocation results in the formation of the BCR-ABL oncogene, expressing two types of abnormal tyrosine kinases and highly specific for CML sufferers. Constitutive activation of these tyrosine kinases leads to dysregulation of intracellular signal transduction, causing proliferation and apoptotic resistance. Imatinib inhibits the activity of several tyrosine kinases, inducing almost complete remission in many CML patients.²

Tyrosine kinase inhibitor therapies are not curative and instances of drug resistance have been documented.¹ This can be due to acquired mutations in target kinases or altered signal transduction pathways to bypass inhibited pathways.¹ To combat this, tyrosine kinase inhibitors are being used in combination with other cancer treatments, such as chemotherapy or monoclonal antibody therapies.¹  Dr Dean has seen treatment-resistant tumours first hand but says that development of resistance is not restricted to TKIs.°

“Any cancer will develop resistance to treatment, no matter what the tumour type is or what treatment is used,” Dr Dean continued, saying that resistance could be combated.

“Development and judicious use of mono- and combination therapies are the keys to making sure we have an effective range of therapeutic options for RCC patients,” he said.

Tyrosine Kinase Inhibitors in Renal Cell Carcinoma

Advanced and metastatic renal cell carcinoma has a very poor prognosis and has proven resistant to conventional chemotherapy agents.¹³ The use of targeted biological therapies has revolutionised the treatment of advanced/metastatic RCC in which the activation of kinase pathways has been noted. Modern treatment of advanced RCC employs multiple receptor tyrosine kinase (rtk) inhibitors such as sunitinib (Sutent) and sorafenib,⁴ and mammalian target of rapamycin (mTOR) inhibitors, such as temsirolimus (Torisel) and everolimus (Afinitor).⁴

Rtk inhibitors target multiple receptor tyrosine kinases associated with cell receptors such as PDGFR and VEGFR, both of which play a role in tumour angiogenesis and tumour cell proliferation. Simultaneous inhibition of multiple pathways can reduce tumour vascularisation and increase tumour cell apoptosis.⁶ The mTOR non-receptor tyrosine kinase is the central regulator of the mTOR signalling pathway, which affects cell growth, proliferation, motility, apoptosis and protein synthesis in response to multiple growth factors (such as EGF, PDGF and IGF).⁶

The National Comprehensive Cancer Network (NCCN) conducts periodic comprehensive reviews of evidence to prepare guidelines specific to different cancer types.⁴ Treatment recommendations are categorised on the basis of quality of evidence and consensus amongst NCCN panel members. These categories are:⁴

• Category 1   – High-level evidence with uniform NCCN consensus that the treatment is appropriate;
• Category 2A – Lower-level evidence with uniform NCCN consensus that the treatment is appropriate;
• Category 2B – Lower-level evidence with NCCN consensus that the treatment is appropriate; and
• Category 3   – Any level of evidence, with major NCCN disagreement as to whether the treatment is appropriate.

The recommendations for first and subsequent systemic therapies (and their associated category) for advanced disease that is medically and surgically unresectable are summarised below. For RCC with clear cell histology, the strength of evidence for use of rtk inhibitors such as sunitinib as first line therapy is sufficient to be given a Category 1 recommendation. First line treatments are listed in order of FDA approval:⁴

^a patients with ≥ 3 predictors of short survival

^b Patients with excellent performance status and normal organ function

^c May include palliative RT, metastasectomy, bisphosphonates or RANK ligand inhibitors for bony metastases

^dAxitinib is not currently registered in Australia

In comparison to conventional systemic therapies TKIs have a favourable side-effect profile according to Dr Dean.

“In general, the side-effects of TKIs are manageable and include fatigue, high blood pressure and loose bowels although dose modification can minimise some of these effects,” he said.

Patient preference and impact on quality of life also favour TKIs.

“Patients prefer TKIs since a typical treatment regimen places much less demand on their time than chemotherapy,” Dr Dean said.

Tyrosine kinase inhibitor therapies have also proven effective in the treatment of a number of other cancer types, including patients with gastrointestinal stromal tumours (GIST’s) with c-KIT gene mutations⁷ and lung cancer patients with HER2 receptors or anaplastic lymphoma kinase mutations.⁸ The benefit of recombinant monoclonal antibody trastuzumab (Herceptin) against the HER2 receptor is also firmly established.⁹ The effective use of tyrosine kinase inhibitors against solid tumours depends on evidence establishing constitutive activation of tyrosine kinase – currently, the role of tyrosine kinase in many solid tumour types is unknown.¹²

Conclusion

The understanding of intracellular signalling pathways has led to the successful targeting of tyrosine kinases in anti-neoplastic therapies. The use of tyrosine kinase inhibitors in renal cell carcinoma is growing, particularly in settings where metastatic disease is established or primary therapies have failed. Utilising the regulatory role of tyrosine kinases is giving rise to a promising new generation of therapies against a wide variety of cancers.

References

1. Braunwald E, Fauci AS, Kasper DL, et al. Harrison’s Principles of Internal Medicine (15th edition). New York: McGraw-Hill Publishing; 2001. [Book]
2. Krause DS, Van Etten RA. Tyrosine kinases as targets for cancer therapy. N Engl J Med. 2005; 353(2):172-87. [Abstract]
3. Arora A, Scholar EM. Role of tyrosine kinase inhibitors in cancer therapy. J Pharmacol Exp Ther. 2005; 315(3):971-9. [Abstract | Full Text]
4. Motzer RJ, Agarwal N, Beard C et al. NCCN Clinical Practice Guidelines in Oncology – Kidney Cancer[Online]. National Comprehensive Cancer Network. 16^th February 2012 [cited 30^th March 2012]. Available from www.nccn.org
5. Druker BJ, Tamura S, Buchdunger E et al. Effects of a selective inhibitor of the Abl tyrosine kinase on the growth of Bcr-Abl positive cells. Nat Med. 1996;5: 561–566. [Abstract]
6. Kapoor A. Inhibition of mTOR in kidney cancer. Curr Oncol. 2009; 16 Suppl 1: S33-9. [Abstract | Full Text]
7. Blay JY, von Mehren M, Blackstein ME. Perspective on updated treatment guidelines for patients with gastrointestinal stromal tumours. Cancer. 2010; 116(22): 5126-37. [Abstract | Full Text]
8. Yuan Y, Liao YM, Hsueh CT, Mirshahidi HR. Novel targeted therapeutics: inhibitors of MDM2, ALK and PARP. J Hematol Oncol. 2011; 4: 16. [Abstract | Full Text]
9. Slamon DJ, Leyland-Jones B, Shak S et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med. 2001;344:783-792 [Abstract | Full Text]
10. Australian Medicines Handbook. Immunomodulators and antineoplastics [online]. AMH 2012 [cited 20^th April 2012]. Available from URL Link.
11. Gherardi E, Birchmeier W, Birchmeier C, Vande Woude G. Targeting MET in cancer: rationale and progress. Nat Rev Cancer. 2012; 12(2):89-103. [Abstract]
12. Madhusudan S, Ganesan TS. Tyrosine kinase inhibitors in cancer therapy. Clin Biochem. 2004; 37(7):618-35. [Abstract]
13. Schöffski P, Dumez H, Clement P et al. Emerging role of tyrosine kinase inhibitors in the treatment of advanced renal cell cancer: a review. Ann Oncol. 2006; 17(8):1185-96. [Abstract „  Full Text]