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New Insights Into Molecular Mechanisms of Sunitinib-Associated Side Effects Molecular Cancer Review Therapeutics New Insights into Molecular Mechanisms of Sunitinib-Associated Side Effects Guadalupe Aparicio-Gallego1, Moises Blanco1, Angelica Figueroa1, Rosario García-Campelo1, Manuel Valladares-Ayerbes1, Enrique Grande-Pulido2, and Luis Anton-Aparicio 1 Abstract The introduction of targeted therapy represents a major advance in the treatment of tumor progression. Targeted agents are a novel therapeutic approach developed to disrupt different cellular signaling pathways. The tyrosine kinase inhibitor sunitinib specifically blocks multiple tyrosine kinase receptors that are involved in the progression of many tumors. Sunitinib is the current standard of care in first-line treatment of advanced renal cell carcinoma, and it is approved in imatinib-intolerant and imatinib-refractory gastrointestinal stromal tumors. However, it is increasingly evident that sunitinib may display collateral effects on other proteins beyond its main target receptors, eliciting undesirable and unexpected adverse events. A better understanding of the molecular mechanisms underlying these undesirable sunitinib-associated side effects will help physicians to maximize efficacy of sunitinib and minimize adverse events. Here, we focus on new insights into molecular mechanisms that may mediate sunitinib-associated adverse events. Mol Cancer Ther; 10(12); 2215–23. Ó2011 AACR. Introduction 2 (KDR), and 3 (FLT4); platelet-derived growth factor receptors A and B (PDGFRA and PDGFRB); the stem cell Tyrosine kinase inhibitors (TKI) are a novel type of factor receptor (cKIT); FMS-like tyrosine kinase 3 (FLT3); drug, designed to target signaling pathways deregulated colony-stimulating factor 1 receptor (CSF-1R); and glial cell in cancer by blocking the ATP-binding pocket of specific line–derived neurotrophic factor receptor [RE arranged receptor tyrosine kinases (RTK). TKIs compete with during transfection (RET); refs. 1–3]. The inhibition of ATP for binding to the intracellular domain of wild-type these RTKs blocks signal transduction, thereby affecting and/or mutant forms of RTKs and, consequently, inhibit various cellular processes, such as tumor growth, tumor signal transduction. progression, angiogenesis, and metastasis (Fig. 1; ref. 4). Although TKIs are designed to target specific RTKs, it is In a phase III study in treatment-na€ve patients increasingly apparent that many TKIs may display unex- with metastatic renal cell carcinoma (RCC), sunitinib pected effects on other kinases and may trigger the significantly doubled median progression-free survival appearance of undesirable side effects. The observed compared with IFN-a and extended median overall sur- incidence of side effects associated with TKIs varies vival beyond 2 years (5, 6). Sunitinib is approved for the between clinical studies, depending on treatment sched- first-line treatment of advanced or metastatic RCC and ule, dosage, patient characteristics, predisposing factors, imatinib-resistant or imatinib-intolerant advanced gastro- secondary diseases, and concurrent administration of intestinal stromal tumors (GIST). other drugs. Moreover, these agents, which do not spe- Although sunitinib therapy is associated with several cifically target tumor cells, are able to act on normal cells, well-characterized side effects, the molecular mechan- eliciting diverse side effects. isms underlying these toxicities remain unclear, but Sunitinib (sunitinib malate; Sutent; Pfizer Inc.) is a they may be related to the additional effect of sunitinib targeted TKI able to inhibit members of the RTK families on nonmalignant (normal) cells that also express containing a split-kinase domain (Fig. 1; ref. 1). These sunitinib targets, or to the cross-talk between different families include VEGF receptor (VEGFR) types 1 (FLT1), intracellular signaling pathways. In this review, we exam- ine the current knowledge about the molecular basis of Authors' Affiliations: 1Clinical Oncology Department and Biomedical sunitinib side effects, including asthenia, fatigue, hair Research Institute (INIBIC), A Coruna~ University Hospital, A Coruna;~ depigmentation, cardiotoxicity, hypothyroidism, hyper- 2 Clinical Oncology Department, Ramon y Cajal University Hospital, Madrid, tension, dermatologic adverse events, and hematologic Spain and gastrointestinal toxicities. Corresponding Author: Luis Anton-Aparicio, Clinical Oncology Depart- ment, A Coruna~ University Hospital, As Xubias 84, 15006 A Coruna,~ Spain. Phone: 34-981-178000; Fax: 34-981-178273; E-mail: Molecular Basis of Fatigue and Asthenia [email protected] doi: 10.1158/1535-7163.MCT-10-1124 Fatigue and asthenia are among the most common Ó2011 American Association for Cancer Research. symptoms experienced by cancer patients, comprising www.aacrjournals.org 2215 Downloaded from mct.aacrjournals.org on September 25, 2021. © 2011 American Association for Cancer Research. Aparicio-Gallego et al. VEGFR1 VEGFR2 VEGFR3 PDGFRα PDGFRβ KIT FLT3 RET (FLT1) (KDR) (FLT4) CH3 CH3 N CH3 O CH3 H3C N N Sunitinib malate Sunitinib malate H O F N CH H3C N H 3 H O N F N CH H H 3 O PI3K/AKT/mTOR RAS/MAPK/MAPKK PKCs N H Antitumor effects Direct effects Antiangiogenic Vascular on cancer cells effects targeting Figure 1. Specific RTKs are blocked by sunitinib (chemical structure shown). Sunitinib is able to block different signaling pathways owing to its action on different RTKs such as PDGFRa and b, KIT, FLT3, RET, and VEGFRs 1, 2, and 3. Sunitinib inhibition of signaling pathways [phosphoinositide 3-kinase (PI3K)/AKT/mTOR, mitogen-activated protein kinase (MAPK), and PKC] triggers different antitumor effects (4). pathologic tiredness, muscle weakness, poor endurance, processes within the cell. As such, AMPK functions as and impaired motor and cognitive function. Fatigue is one an energy sensor protein that is activated in response of the most commonly reported side effects of sunitinib to an increased cellular AMP-to-ATP ratio, occurr- treatment, although the degree of fatigue and its impact on ing, for example, during nutrient starvation (pooled quality of life is variable (7). In sunitinib phase III clinical data in sunitinib-treated RCC show that grade 3–4 trials, 34% to 62% of patients exhibited fatigue of any grade, anorexia occurs in approximately 3% of patients; ref. 9) with 5% to 15% reporting grade 3 to 4 fatigue. Asthenia was or vigorous muscular exercise. The serine-threonine less common, with an all-grade frequency of 12% to 25% kinase LKB1 is an important component of the AMPK and grade 3 to 4 frequency of 3% to 11% (5, 6, 8, 9). pathway and modulates AMPK activity (12). Both The precise clinical mechanisms responsible for causing the AMPK and LKB1 kinases are potential targets for fatigue and asthenia are unknown but are likely to work sunitinib (13), which may, therefore, impair the signal- through similar pathways. Cancer-related fatigue is ing pathway responsible for maintaining the correct known to involve both peripheral (originating in the energy cellular balance, resulting in fatigue and/or muscles and related tissues) and central (developing in asthenia. the CNS) mechanisms, and several possible pathophysio- logic pathways have been explored (10). Looking at Glucose transporters RCC specifically, a study in diabetic patients showed that Glucose uptake occurs through facilitative diffusion in sunitinib triggers a decrease in blood glucose levels (11), a process mediated by plasma membrane glucose trans- which may be involved in the induction of fatigue and/or porters. Contractile activity in the muscles triggers glu- asthenia. However, as both diabetic and nondiabetic cose uptake in an insulin-independent manner. Nitric patients treated with sunitinib experience fatigue and oxide synthase (NOS) is also stimulated in muscles in asthenia (11), other mechanisms may also be involved, response to contractile activity, increasing nitric oxide as discussed below. (NO) production. Some research suggests that inhibition of NO production can block the ability of exercise to AMP-activated protein kinase stimulate glucose transport (14). Other studies have AMP-activated protein kinase (AMPK) is critical shown that endothelial NOS is stimulated in a VEGFR- in ensuring a balance between anabolic and catabolic dependent manner (15). 2216 Mol Cancer Ther; 10(12) December 2011 Molecular Cancer Therapeutics Downloaded from mct.aacrjournals.org on September 25, 2021. © 2011 American Association for Cancer Research. Molecular Basis of Sunitinib Toxicity In light of these data, sunitinib-mediated inhibition of Molecular Basis of Sunitinib Cardiotoxicity VEGFR may trigger inhibition of NOS and reduced pro- duction of NO, resulting in a reduction in glucose uptake. The reported incidence of cardiotoxicity (primarily In addition, as VEGFR can convey its signal through left ventricular dysfunction) with sunitinib varies from protein kinase C (PKC), sunitinib may indirectly inhibit approximately 11% to 16% in the phase III studies in PKC activity. PKC mediates calcium-mediated glucose patients with GIST or metastatic RCC, respectively uptake in the muscle, and its inhibition could impair (4, 7, 8). The molecular mechanisms that may explain insulin-dependent glucose uptake to the muscle. sunitinib-induced cardiomyocyte cytotoxicity are reviewed below. Circadian rhythm disruption Ligands of growth factors may also play a role in Angiogenesis circadian rhythm disruption, which can lead to symptom Among the targets of sunitinib, only PDGFRs are clusters, including fatigue, appetite
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