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A Rare Case of Sunitinib-Induced Rhabdomyolysis in Renal Cell Carcinoma

A Rare Case of Sunitinib-Induced Rhabdomyolysis in Renal Cell Carcinoma Hindawi Case Reports in Oncological Medicine Volume 2018, Article ID 3808523, 4 pages https://doi.org/10.1155/2018/3808523 Case Report A Rare Case of Sunitinib-Induced Rhabdomyolysis in Renal Cell Carcinoma 1 1 2 3 Andrew D. Liman , Vida A. Passero, Agnes K. Liman , and Jenna Shields Hematology and Oncology, VA Pittsburgh Healthcare System, University of Pittsburgh School of Medicine, Pittsburgh, PA 15240, USA Laboratory and Pathology, VA Pittsburgh Healthcare System, University of Pittsburgh School of Medicine, Pittsburgh, PA 15240, USA Pharmacy, VA Pittsburgh Healthcare System, Pittsburgh, PA 15240, USA Correspondence should be addressed to Andrew D. Liman; andrew.liman@va.gov Received 24 March 2018; Accepted 2 July 2018; Published 19 July 2018 Academic Editor: Jose I. Mayordomo Copyright © 2018 Andrew D. Liman et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. We report a rare case of metastatic renal cell carcinoma (RCC) in a patient who developed rhabdomyolysis while on sunitinib. He was admitted to the hospital due to muscle weakness, fatigue, poor oral intake, and difficulty swallowing in March 2017. He was found to have pancytopenia, liver failure, kidney failure, high uric acid, and increased creatine phosphokinase of more than 5000. He quickly developed lactic acidosis and acute respiratory failure. He was transferred to the ICU, but his condition declined rapidly. He died 3 days later. In this article we discussed about sunitinib-mediated inhibition of adenosine monophosphate kinase (AMPK) as a possible pathophysiology of rhabdomyolysis. Our case is the third sunitinib-induced rhabdomyolysis reported in the literature. 1. Introduction Sunitinib is an oral multitargeted drug against the VEGF receptors (VEGFRs) 1, 2, and 3; platelet-derived growth fac- Kidney cancer is among the ten most frequently diagnosed tor receptors (PDGFRs); and other tyrosine kinases. Suniti- cancers in men and women in the United States, with more nib has been associated with higher response rate, longer than an estimated 62,000 new cases in 2016. The prognosis progression-free survival, and overall survival than interferon has historically been poor, with current 5-year survival rates alfa [1]. of 74% overall, decreasing to 53% among patients with locor- egional (stage III) disease and 8% among patients with meta- 2. Case Presentation static disease. Although more than 14,000 patients die from kidney cancer each year, there has been considerable prog- The patient is a 71-year-old white male who was found to ress in the systemic treatment of metastatic RCC in the past have a 3.5 cm right kidney mass and had been followed by 20 years. Clear cell RCC makes up approximately 70% of the urology team closely at VA Pittsburgh Healthcare Sys- RCCs [1]. tem. Urine cytology was suspicious for malignant cells. He In 2005 and 2006, the Food and Drug Administration underwent a radical right nephrectomy on February 3, (FDA) approved multikinase inhibitors sorafenib and suniti- 2014. Pathology showed clear cell RCC. The tumor was nib, respectively. The approval of five other antiangiogenic located at the lower pole with a size of 4.5 cm (pT1b) and drugs (pazopanib, axitinib, bevacizumab, cabozantinib, and Fuhrman nuclear grade 2. All margins were not involved by lenvatinib) followed. Two mTOR inhibitors, temsirolimus carcinoma, and there was no vascular invasion. He had been and everolimus, were approved in later years. The immune followed with a regular CT scan every year. He was found to checkpoint inhibitor nivolumab showed benefit in random- have small bilateral lung metastasis and lymphadenopathy in ized phase 3 trials and was approved by the FDA in 2015. 2016. The PET scan on April 26, 2016, revealed FDG activity 2 Case Reports in Oncological Medicine in the lung and hilar and mediastinal lymph nodes. He Table 1 underwent endobronchial ultrasound biopsy of the mediasti- Day 1 Day 2 Day 3 Day 4 nal lymph node which confirmed to be metastatic from clear LAB 2017 (3/29) (3/30) (3/31) (4/1) cell RCC. Due to his comorbidities and mild thrombocytope- WBC (K/cmm) 5.4 6.4 7.5 5.3 nia, we started him on lower dose sunitinib at 37.5 mg per oral daily ×4 weeks every 6 weeks in May 2016. In total, he HGB (g/dL) 14.7 14 14 12.6 received 7 cycles of sunitinib. He had been followed every 6 Platelet (K/cmm) 13 17 18 13 weeks in the clinic. He only developed fatigue due to mild Potassium (mmol/L) 5.8 6.1 4.8 4.0 hypothyroidism for which he received levothyroxine. During AST (IU/L) 462 1984 2032 2450 the follow-up, he was found to have worsening thrombocyto- ALT (IU/L) 351 1579 2277 2197 penia with platelet counts in the range of 60,000 to 90,000. A BUN (mg/dL) 29 30 31 31 follow-up CT scan and PET scan in October 2016 showed Creatinine (mg/dL) 2.0 2.0 2.3 2.2 improvement of the lung metastasis and lymphadenopathy. Bilirubin (mg/dL) 4.1 4.7 4.0 4.0 He was last seen in the clinic on March 13, 2017. He was admitted on March 29, 2017, due to muscle weak- Uric acid (mg/dL) — 12.1 —— ness, fatigue, poor oral intake, and difficulty swallowing for 2 Lactic acid (mmol/L) —— 9.4 10.5 weeks. During admission, his platelet count was found to be CPK (IU/L) 1393 3667 5149 3582 13,000, serum creatinine 2.3, total bilirubin 4, AST/ Troponin (ng/mL) 0.10 0.11 0.12 — ALT > 2000, INR 2.9, calcium 7.5, creatine phosphokinase (CPK) > 5000, and uric acid 12 (see Table 1). Sunitinib was discontinued on the first day of admission. CT head revealed sunitinib trial [3, 4]. Sunitinib inhibits VEGFRs 1, 2, and 3; no evidence of metastatic disease. Chest X-ray did not show PDGFRs, and other tyrosine kinases. PDGFRs, which are evidence of infiltration or effusion. Echocardiogram showed expressed in cardiomyocytes, have been reported to serve a severe global hypokinesia with LVEF of 30–35%. His LVEF protective role in the heart exposed to ischemic injury. How- was 55% prior to starting on sunitinib. He quickly developed ever, the study by Edelberg et al. employed exogenous lactic acidosis and acute respiratory failure. In the intensive administration of PDGF to the heart [5]. But it was unclear care unit, he received bicarbonate, high-dose oxygen, furose- whether the inhibition of endogenous PDGFRs by sunitinib mide, and treatment for hyperkalemia. Despite all treatment would induce cardiotoxicity. support, he continued to decline. His family chose to deesca- Kerkela et al. obtained an endomyocardial biopsy in a late care, and he died on April 1, 2017. patient with RCC who developed acute decompensated sys- tolic heart failure after 11 months of sunitinib treatment (37.5 mg daily dose) [6]. Prior to therapy, the LVEF was 3. Discussion 65%. When the patient presented with heart failure, the Sunitinib is one of the standards of care therapy in patients LVEF had decreased to 20–25%. Transmission electron with metastatic RCC with good or intermediate risk factors microscopy revealed widespread and severe structural alter- ations in mitochondria which included markedly swollen based on Memorial Sloan Kettering Cancer Center (MSKCC) risk factor criteria. Our patient had achieved a good response mitochondria. The authors identified in the human heart in the lung metastasis and hilar and mediastinal lymphade- biopsy that off-target inhibition by sunitinib demonstrated disruption of the mitochondrial architecture and an IC50 nopathy; however, after 10 months on sunitinib, he was admitted with anemia, worsening thrombocytopenia, hyper- for adenosine monophosphate kinase (AMPK) inhibition as uricemia, acute renal failure, and evidence of myocardial fail- low as 0.2 mM [6]. ure. He was found to have severe global myocardial AMPK is a critical kinase in times of energy depletion hypokinesia with LVEF decreased from 55% prior to suniti- when adenosine triphosphate (ATP) levels decline and aden- osine monophosphate (AMP) levels increase. AMPK activa- nib to 30% to 35% after initiating treatment with sunitinib. The diagnosis of sunitinib-induced rhabdomyolysis is based tion blocks energy-consuming pathways, including protein on the fact that he developed multiorgan failure and cardio- translation/synthesis and fatty acid synthesis. AMPK acti- myopathy with CPK increased to more than 5000. Sunitinib vates energy-generating pathways by increasing fatty acid is the only plausible cause to his clinical presentation. Rug- oxidation via phosphorylation of acetyl-coA carboxylase 2 (ACC2) and glycolysis via activation of phosphofructo-2- geri et al. reported two cases of rhabdomyolysis while on sunitinib in metastatic RCC [2]. Both patients developed kinase (PFK) (Figure 1(a)). Sunitinib-mediated inhibition of exactly the same clinical and laboratory abnormalities like AMPK could release these energy-consuming pathways and our patient with high AST/ALT and very high CPK. One prevent activation of energy-generating pathways, exacerbat- patient died three days later, and the other patient survived ing the energy rundown in the cell (Figure 1(b)) [6, 7]. It has been suggested that modification or reduction of sunitinib after emergent hemodialysis for his anuria [2]. Side effects of sunitinib include, but are not limited to, dose to no longer target AMPK might reduce cardiotoxicity. fatigue, nausea, diarrhea, hypertension, hypothyroidism, car- Hohenegger also proposed the same mechanism that diac toxicity, and skin toxicity. A decrease in the LVEF is one suggests sunitinib could interfere with fatty acid oxidation of the main cardiac toxicities of sunitinib. Grade 3 LVEF and glycolysis. Under stress, AMPK activity usually acts as a rescue pathway. Sunitinib inhibits AMPK thus causing a decline was reported in 3% in phase III first-line clinical Case Reports in Oncological Medicine 3 FA synthesis ACC1 Mitochondrial ACC2 FA oxydation injury due to ATP AMPK ATP energy stress PFK Glycolysis (a) ACC1 FA synthesis Mitochondrial ACC2 FA oxydation injury due to ATP AMPK ATP energy stress PFK Glycolysis Sunitinib (b) Figure 1: (a) Activation of AMP-kinase leads to the increase in ATP. Energy stress causes a decrease in ATP and in turn leads to activation of AMP-kinase. This will induce energy-generating pathways by rapid phosphorylation of acetyl coA carboxylases 1 and 2 (ACC1 and ACC2) and phosphofructokinase (PFK), which lead to decreased fatty acid synthesis, increased fatty acid oxidation, and increased glycolysis. This mechanism is to restore energy homeostasis. (b) Inhibition of AMP-kinase by sunitinib leads to a decrease in ATP. In the presence of sunitinib, ATP cannot bind to AMPK. This will prevent the activation of energy generating pathways and exacerbate energy-consuming pathways. Ca2+ influx Muscle cell Sarcomere/ Ca2+ myofibrils channel receptor Ca2+ Calpain 3 Sarcoplasmic reticulum ATP Ubiquitin Mitochondria AMP-kinase Proteasome Sunitinib Figure 2: Sunitinib inhibits intracellular AMP-kinase and increase myoplasmic Ca2+. Accumulation of Ca2+ will activate calpain 3 kinase that in turn cause degradation of myofibrils. Ubiquitin ligases will ubiquitinate the peptides and target them for degradation in the proteasome. decline in intracellular ATP and elevation in myoplasmic proteins that participate in Ca2+ homeostasis and thereby Ca2+. Sufficient ATP supply by mitochondrial respiratory aggravate myoplasmic Ca2+ overload. The skeletal muscle- chain fails, and as a consequence, extrusion of Ca2+ to the specific calpain 3 protease may contribute a further mecha- extracellular space is reduced [8, 9]. Long-lasting Ca2+ eleva- nism helping to explain the destruction of the myofibrils tions activate calpain proteases, which further degrade [10]. Calpain 3 is anchored to the sarcomere which performs 4 Case Reports in Oncological Medicine the initial proteolytic cleavage that allows ubiquitin ligases to [5] J. M. Edelberg, S. H. Lee, M. Kaur et al., “Platelet-derived growth factor-AB limits the extent of myocardial infarction ubiquitinate the peptides and target them for degradation in in a rat model: feasibility of restoring impaired angiogenic the proteasome (Figure 2) [11]. capacity in the aging heart,” Circulation, vol. 105, no. 5, Severe global myocardial hypokinesia and increase in pp. 608–613, 2002. CPK due to destruction in myofibrils are the most important [6] R. Kerkela, K. C. Woulfe, J. B. Durand et al., “Sunitinib- clinical presentation of sunitinib-induced rhabdomyolysis. induced cardiotoxicity is mediated by off-target inhibition of As reported in the two other cases by Ruggeri et al., CPK AMP-activated protein kinase,” Clinical and Translational could be as high as 3000 to 5000. Myoglobin can be found Science, vol. 2, no. 1, pp. 15–25, 2009. in urine, but with a short half-life (about two to three hours). [7] M. C. Towler and D. G. Hardie, “AMP-activated protein Serum CPK is a better marker for the diagnosis of rhabdomy- kinase in metabolic control and insulin signaling,” Circulation olysis. CPK is active in skeletal muscles (CPK-MM) and Research, vol. 100, no. 3, pp. 328–341, 2007. catalyzes the transportation of one phosphate group from [8] J. R. López, M. A. Gonzalez, B. Rojas, J. R. López, and A. Terzic, creatinine (C) to ADP, resulting in ATP. CPK is elevated in 2+ “Myoplasmic Ca concentration during exertional rhabdo- the first 12 hours after the onset of rhabdomyolysis, peaks myolysis,” The Lancet, vol. 345, no. 8947, pp. 424-425, 1995. within the first three days, and returns to the baseline level [9] M. Hohenegger, “Drug induced rhabdomyolysis,” Current at three to five days after the injury. The half-life of CPK is Opinion in Pharmacology, vol. 12, no. 3, pp. 335–339, 2012. 1.5 days. Therefore, CPK is a more reliable marker than myo- [10] R. M. Murphy, “Calpains, skeletal muscle function and exer- globin in the diagnosis of muscular damage [12]. cise,” Clinical and Experimental Pharmacology and Physiology, vol. 37, no. 3, pp. 385–391, 2010. 4. Conclusion [11] J. S. Beckmann and M. Spencer, “Calpain 3, the “gatekeeper” of proper sarcomere assembly, turnover and maintenance,” Neu- Sunitinib-induced rhabdomyolysis is a very rare occurrence. romuscular Disorders, vol. 18, no. 12, pp. 913–921, 2008. Rhabdomyolysis presents with rapid deterioration of clinical [12] M. H. Zhang, “Rhabdomyolosis and its pathogenesis,” World condition due to liver failure, kidney failure, global hypoki- Journal of Emergency Medicine, vol. 3, no. 1, pp. 11–15, 2012. nesia of myocardium, very high CPK, hyperuricemia, and lactic acidosis that could lead to death. Inhibition of AMPK has been reported as the possible pathophysiology of this toxicity. Initial recognition of this toxicity is critical to ensure timely management. Consent Verbal consent was obtained from the patient’s family. Disclosure This abstract was presented as a Poster Presentation at the 13th Annual Meeting of Association of Veteran Affairs Hematology and Oncology (AVAHO) in Denver, Colorado, USA, on September 14–17, 2017. Conflicts of Interest All authors have no conflict of interests. References [1] T. K. Choueiri and R. J. Motzer, “Systemic therapy for metasta- tic renal-cell carcinoma,” The New England Journal of Medi- cine, vol. 376, no. 4, pp. 354–366, 2017. [2] E. M. Ruggeri, F. L. Cecere, L. Moscetti, L. Doni, D. Padalino, and F. Di Costanzo, “Severe rhabdomyolysis during sunitinib treatment of metastatic renal cell carcinoma. A report of two cases,” Annals of Oncology, vol. 21, no. 9, pp. 1926-1927, 2010. [3] T. F. Chu, M. A. Rupnick, R. Kerkela et al., “Cardiotoxicity associated with tyrosine kinase inhibitor sunitinib,” The Lancet, vol. 370, no. 9604, pp. 2011–2019, 2007. [4] T. A. Schmid and M. E. Gore, “Sunitinib in the treatment of metastatic renal cell carcinoma,” Therapeutic Advances in Urology, vol. 8, no. 6, pp. 348–371, 2016. 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A Rare Case of Sunitinib-Induced Rhabdomyolysis in Renal Cell Carcinoma

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Hindawi Case Reports in Oncological Medicine Volume 2018, Article ID 3808523, 4 pages https://doi.org/10.1155/2018/3808523 Case Report A Rare Case of Sunitinib-Induced Rhabdomyolysis in Renal Cell Carcinoma 1 1 2 3 Andrew D. Liman , Vida A. Passero, Agnes K. Liman , and Jenna Shields Hematology and Oncology, VA Pittsburgh Healthcare System, University of Pittsburgh School of Medicine, Pittsburgh, PA 15240, USA Laboratory and Pathology, VA Pittsburgh Healthcare System, University of Pittsburgh School of Medicine, Pittsburgh, PA 15240, USA Pharmacy, VA Pittsburgh Healthcare System, Pittsburgh, PA 15240, USA Correspondence should be addressed to Andrew D. Liman; andrew.liman@va.gov Received 24 March 2018; Accepted 2 July 2018; Published 19 July 2018 Academic Editor: Jose I. Mayordomo Copyright © 2018 Andrew D. Liman et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. We report a rare case of metastatic renal cell carcinoma (RCC) in a patient who developed rhabdomyolysis while on sunitinib. He was admitted to the hospital due to muscle weakness, fatigue, poor oral intake, and difficulty swallowing in March 2017. He was found to have pancytopenia, liver failure, kidney failure, high uric acid, and increased creatine phosphokinase of more than 5000. He quickly developed lactic acidosis and acute respiratory failure. He was transferred to the ICU, but his condition declined rapidly. He died 3 days later. In this article we discussed about sunitinib-mediated inhibition of adenosine monophosphate kinase (AMPK) as a possible pathophysiology of rhabdomyolysis. Our case is the third sunitinib-induced rhabdomyolysis reported in the literature. 1. Introduction Sunitinib is an oral multitargeted drug against the VEGF receptors (VEGFRs) 1, 2, and 3; platelet-derived growth fac- Kidney cancer is among the ten most frequently diagnosed tor receptors (PDGFRs); and other tyrosine kinases. Suniti- cancers in men and women in the United States, with more nib has been associated with higher response rate, longer than an estimated 62,000 new cases in 2016. The prognosis progression-free survival, and overall survival than interferon has historically been poor, with current 5-year survival rates alfa [1]. of 74% overall, decreasing to 53% among patients with locor- egional (stage III) disease and 8% among patients with meta- 2. Case Presentation static disease. Although more than 14,000 patients die from kidney cancer each year, there has been considerable prog- The patient is a 71-year-old white male who was found to ress in the systemic treatment of metastatic RCC in the past have a 3.5 cm right kidney mass and had been followed by 20 years. Clear cell RCC makes up approximately 70% of the urology team closely at VA Pittsburgh Healthcare Sys- RCCs [1]. tem. Urine cytology was suspicious for malignant cells. He In 2005 and 2006, the Food and Drug Administration underwent a radical right nephrectomy on February 3, (FDA) approved multikinase inhibitors sorafenib and suniti- 2014. Pathology showed clear cell RCC. The tumor was nib, respectively. The approval of five other antiangiogenic located at the lower pole with a size of 4.5 cm (pT1b) and drugs (pazopanib, axitinib, bevacizumab, cabozantinib, and Fuhrman nuclear grade 2. All margins were not involved by lenvatinib) followed. Two mTOR inhibitors, temsirolimus carcinoma, and there was no vascular invasion. He had been and everolimus, were approved in later years. The immune followed with a regular CT scan every year. He was found to checkpoint inhibitor nivolumab showed benefit in random- have small bilateral lung metastasis and lymphadenopathy in ized phase 3 trials and was approved by the FDA in 2015. 2016. The PET scan on April 26, 2016, revealed FDG activity 2 Case Reports in Oncological Medicine in the lung and hilar and mediastinal lymph nodes. He Table 1 underwent endobronchial ultrasound biopsy of the mediasti- Day 1 Day 2 Day 3 Day 4 nal lymph node which confirmed to be metastatic from clear LAB 2017 (3/29) (3/30) (3/31) (4/1) cell RCC. Due to his comorbidities and mild thrombocytope- WBC (K/cmm) 5.4 6.4 7.5 5.3 nia, we started him on lower dose sunitinib at 37.5 mg per oral daily ×4 weeks every 6 weeks in May 2016. In total, he HGB (g/dL) 14.7 14 14 12.6 received 7 cycles of sunitinib. He had been followed every 6 Platelet (K/cmm) 13 17 18 13 weeks in the clinic. He only developed fatigue due to mild Potassium (mmol/L) 5.8 6.1 4.8 4.0 hypothyroidism for which he received levothyroxine. During AST (IU/L) 462 1984 2032 2450 the follow-up, he was found to have worsening thrombocyto- ALT (IU/L) 351 1579 2277 2197 penia with platelet counts in the range of 60,000 to 90,000. A BUN (mg/dL) 29 30 31 31 follow-up CT scan and PET scan in October 2016 showed Creatinine (mg/dL) 2.0 2.0 2.3 2.2 improvement of the lung metastasis and lymphadenopathy. Bilirubin (mg/dL) 4.1 4.7 4.0 4.0 He was last seen in the clinic on March 13, 2017. He was admitted on March 29, 2017, due to muscle weak- Uric acid (mg/dL) — 12.1 —— ness, fatigue, poor oral intake, and difficulty swallowing for 2 Lactic acid (mmol/L) —— 9.4 10.5 weeks. During admission, his platelet count was found to be CPK (IU/L) 1393 3667 5149 3582 13,000, serum creatinine 2.3, total bilirubin 4, AST/ Troponin (ng/mL) 0.10 0.11 0.12 — ALT > 2000, INR 2.9, calcium 7.5, creatine phosphokinase (CPK) > 5000, and uric acid 12 (see Table 1). Sunitinib was discontinued on the first day of admission. CT head revealed sunitinib trial [3, 4]. Sunitinib inhibits VEGFRs 1, 2, and 3; no evidence of metastatic disease. Chest X-ray did not show PDGFRs, and other tyrosine kinases. PDGFRs, which are evidence of infiltration or effusion. Echocardiogram showed expressed in cardiomyocytes, have been reported to serve a severe global hypokinesia with LVEF of 30–35%. His LVEF protective role in the heart exposed to ischemic injury. How- was 55% prior to starting on sunitinib. He quickly developed ever, the study by Edelberg et al. employed exogenous lactic acidosis and acute respiratory failure. In the intensive administration of PDGF to the heart [5]. But it was unclear care unit, he received bicarbonate, high-dose oxygen, furose- whether the inhibition of endogenous PDGFRs by sunitinib mide, and treatment for hyperkalemia. Despite all treatment would induce cardiotoxicity. support, he continued to decline. His family chose to deesca- Kerkela et al. obtained an endomyocardial biopsy in a late care, and he died on April 1, 2017. patient with RCC who developed acute decompensated sys- tolic heart failure after 11 months of sunitinib treatment (37.5 mg daily dose) [6]. Prior to therapy, the LVEF was 3. Discussion 65%. When the patient presented with heart failure, the Sunitinib is one of the standards of care therapy in patients LVEF had decreased to 20–25%. Transmission electron with metastatic RCC with good or intermediate risk factors microscopy revealed widespread and severe structural alter- ations in mitochondria which included markedly swollen based on Memorial Sloan Kettering Cancer Center (MSKCC) risk factor criteria. Our patient had achieved a good response mitochondria. The authors identified in the human heart in the lung metastasis and hilar and mediastinal lymphade- biopsy that off-target inhibition by sunitinib demonstrated disruption of the mitochondrial architecture and an IC50 nopathy; however, after 10 months on sunitinib, he was admitted with anemia, worsening thrombocytopenia, hyper- for adenosine monophosphate kinase (AMPK) inhibition as uricemia, acute renal failure, and evidence of myocardial fail- low as 0.2 mM [6]. ure. He was found to have severe global myocardial AMPK is a critical kinase in times of energy depletion hypokinesia with LVEF decreased from 55% prior to suniti- when adenosine triphosphate (ATP) levels decline and aden- osine monophosphate (AMP) levels increase. AMPK activa- nib to 30% to 35% after initiating treatment with sunitinib. The diagnosis of sunitinib-induced rhabdomyolysis is based tion blocks energy-consuming pathways, including protein on the fact that he developed multiorgan failure and cardio- translation/synthesis and fatty acid synthesis. AMPK acti- myopathy with CPK increased to more than 5000. Sunitinib vates energy-generating pathways by increasing fatty acid is the only plausible cause to his clinical presentation. Rug- oxidation via phosphorylation of acetyl-coA carboxylase 2 (ACC2) and glycolysis via activation of phosphofructo-2- geri et al. reported two cases of rhabdomyolysis while on sunitinib in metastatic RCC [2]. Both patients developed kinase (PFK) (Figure 1(a)). Sunitinib-mediated inhibition of exactly the same clinical and laboratory abnormalities like AMPK could release these energy-consuming pathways and our patient with high AST/ALT and very high CPK. One prevent activation of energy-generating pathways, exacerbat- patient died three days later, and the other patient survived ing the energy rundown in the cell (Figure 1(b)) [6, 7]. It has been suggested that modification or reduction of sunitinib after emergent hemodialysis for his anuria [2]. Side effects of sunitinib include, but are not limited to, dose to no longer target AMPK might reduce cardiotoxicity. fatigue, nausea, diarrhea, hypertension, hypothyroidism, car- Hohenegger also proposed the same mechanism that diac toxicity, and skin toxicity. A decrease in the LVEF is one suggests sunitinib could interfere with fatty acid oxidation of the main cardiac toxicities of sunitinib. Grade 3 LVEF and glycolysis. Under stress, AMPK activity usually acts as a rescue pathway. Sunitinib inhibits AMPK thus causing a decline was reported in 3% in phase III first-line clinical Case Reports in Oncological Medicine 3 FA synthesis ACC1 Mitochondrial ACC2 FA oxydation injury due to ATP AMPK ATP energy stress PFK Glycolysis (a) ACC1 FA synthesis Mitochondrial ACC2 FA oxydation injury due to ATP AMPK ATP energy stress PFK Glycolysis Sunitinib (b) Figure 1: (a) Activation of AMP-kinase leads to the increase in ATP. Energy stress causes a decrease in ATP and in turn leads to activation of AMP-kinase. This will induce energy-generating pathways by rapid phosphorylation of acetyl coA carboxylases 1 and 2 (ACC1 and ACC2) and phosphofructokinase (PFK), which lead to decreased fatty acid synthesis, increased fatty acid oxidation, and increased glycolysis. This mechanism is to restore energy homeostasis. (b) Inhibition of AMP-kinase by sunitinib leads to a decrease in ATP. In the presence of sunitinib, ATP cannot bind to AMPK. This will prevent the activation of energy generating pathways and exacerbate energy-consuming pathways. Ca2+ influx Muscle cell Sarcomere/ Ca2+ myofibrils channel receptor Ca2+ Calpain 3 Sarcoplasmic reticulum ATP Ubiquitin Mitochondria AMP-kinase Proteasome Sunitinib Figure 2: Sunitinib inhibits intracellular AMP-kinase and increase myoplasmic Ca2+. Accumulation of Ca2+ will activate calpain 3 kinase that in turn cause degradation of myofibrils. Ubiquitin ligases will ubiquitinate the peptides and target them for degradation in the proteasome. decline in intracellular ATP and elevation in myoplasmic proteins that participate in Ca2+ homeostasis and thereby Ca2+. Sufficient ATP supply by mitochondrial respiratory aggravate myoplasmic Ca2+ overload. The skeletal muscle- chain fails, and as a consequence, extrusion of Ca2+ to the specific calpain 3 protease may contribute a further mecha- extracellular space is reduced [8, 9]. Long-lasting Ca2+ eleva- nism helping to explain the destruction of the myofibrils tions activate calpain proteases, which further degrade [10]. Calpain 3 is anchored to the sarcomere which performs 4 Case Reports in Oncological Medicine the initial proteolytic cleavage that allows ubiquitin ligases to [5] J. M. Edelberg, S. H. Lee, M. Kaur et al., “Platelet-derived growth factor-AB limits the extent of myocardial infarction ubiquitinate the peptides and target them for degradation in in a rat model: feasibility of restoring impaired angiogenic the proteasome (Figure 2) [11]. capacity in the aging heart,” Circulation, vol. 105, no. 5, Severe global myocardial hypokinesia and increase in pp. 608–613, 2002. CPK due to destruction in myofibrils are the most important [6] R. Kerkela, K. C. Woulfe, J. B. Durand et al., “Sunitinib- clinical presentation of sunitinib-induced rhabdomyolysis. induced cardiotoxicity is mediated by off-target inhibition of As reported in the two other cases by Ruggeri et al., CPK AMP-activated protein kinase,” Clinical and Translational could be as high as 3000 to 5000. Myoglobin can be found Science, vol. 2, no. 1, pp. 15–25, 2009. in urine, but with a short half-life (about two to three hours). [7] M. C. Towler and D. G. Hardie, “AMP-activated protein Serum CPK is a better marker for the diagnosis of rhabdomy- kinase in metabolic control and insulin signaling,” Circulation olysis. CPK is active in skeletal muscles (CPK-MM) and Research, vol. 100, no. 3, pp. 328–341, 2007. catalyzes the transportation of one phosphate group from [8] J. R. López, M. A. Gonzalez, B. Rojas, J. R. López, and A. Terzic, creatinine (C) to ADP, resulting in ATP. CPK is elevated in 2+ “Myoplasmic Ca concentration during exertional rhabdo- the first 12 hours after the onset of rhabdomyolysis, peaks myolysis,” The Lancet, vol. 345, no. 8947, pp. 424-425, 1995. within the first three days, and returns to the baseline level [9] M. Hohenegger, “Drug induced rhabdomyolysis,” Current at three to five days after the injury. The half-life of CPK is Opinion in Pharmacology, vol. 12, no. 3, pp. 335–339, 2012. 1.5 days. Therefore, CPK is a more reliable marker than myo- [10] R. M. Murphy, “Calpains, skeletal muscle function and exer- globin in the diagnosis of muscular damage [12]. cise,” Clinical and Experimental Pharmacology and Physiology, vol. 37, no. 3, pp. 385–391, 2010. 4. Conclusion [11] J. S. Beckmann and M. Spencer, “Calpain 3, the “gatekeeper” of proper sarcomere assembly, turnover and maintenance,” Neu- Sunitinib-induced rhabdomyolysis is a very rare occurrence. romuscular Disorders, vol. 18, no. 12, pp. 913–921, 2008. Rhabdomyolysis presents with rapid deterioration of clinical [12] M. H. Zhang, “Rhabdomyolosis and its pathogenesis,” World condition due to liver failure, kidney failure, global hypoki- Journal of Emergency Medicine, vol. 3, no. 1, pp. 11–15, 2012. nesia of myocardium, very high CPK, hyperuricemia, and lactic acidosis that could lead to death. Inhibition of AMPK has been reported as the possible pathophysiology of this toxicity. Initial recognition of this toxicity is critical to ensure timely management. Consent Verbal consent was obtained from the patient’s family. Disclosure This abstract was presented as a Poster Presentation at the 13th Annual Meeting of Association of Veteran Affairs Hematology and Oncology (AVAHO) in Denver, Colorado, USA, on September 14–17, 2017. Conflicts of Interest All authors have no conflict of interests. References [1] T. K. Choueiri and R. J. Motzer, “Systemic therapy for metasta- tic renal-cell carcinoma,” The New England Journal of Medi- cine, vol. 376, no. 4, pp. 354–366, 2017. [2] E. M. Ruggeri, F. L. Cecere, L. Moscetti, L. Doni, D. Padalino, and F. Di Costanzo, “Severe rhabdomyolysis during sunitinib treatment of metastatic renal cell carcinoma. A report of two cases,” Annals of Oncology, vol. 21, no. 9, pp. 1926-1927, 2010. [3] T. F. Chu, M. A. Rupnick, R. Kerkela et al., “Cardiotoxicity associated with tyrosine kinase inhibitor sunitinib,” The Lancet, vol. 370, no. 9604, pp. 2011–2019, 2007. [4] T. A. Schmid and M. E. Gore, “Sunitinib in the treatment of metastatic renal cell carcinoma,” Therapeutic Advances in Urology, vol. 8, no. 6, pp. 348–371, 2016. 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