Author + information
- Ana Barac, MD, PhD∗ ()
- ↵∗Reprint requests and correspondence:
Dr. Ana Barac, Division of Cardiology, MedStar Washington Hospital Center, 110 Irving Street NW, Suite NA 1235, Washington, DC 20010.
An increasing number of oncology patients are seen by cardiologists every day, and a dilemma facing both the cardiologist and the oncologist is how to predict risk of cardiac toxicity. Efficacious therapies targeting malignant cancers are now recognized as potentially harmful for the heart. Many of the novel cancer therapies include kinase inhibitors (KIs). Protein kinases are enzymes that add a phosphate to proteins and regulate critical cell functions such as cell growth, death, and survival. Therapeutic targeting of kinases expressed in cancer, or the cancer kinome, with either humanized monoclonal antibodies or with KIs has revolutionized the treatment of many cancers, leading to improvements in patient survival and prognosis.
In this issue of the Journal, Pfister et al. (1) insightfully activate a kinase and show how it is beneficial and protective for the heart. This approach is insightful because the cancer literature has shown therapeutic efficacy in inhibiting this very kinase to treat cancer. The increasing knowledge of the cancer and the heart kinomes allow us to better understand and prevent cardiotoxicity related to cancer therapies as well as to identify novel molecular targets to treat heart disease.
The study by Pfister et al. (1) joins the evolving field of cardio-oncology research by exploring the role of FMS-like tyrosine kinase (FLT3) and FLT3 ligand (FL) signaling in the heart. It found that intramyocardial injection of FL, following the ligation of the left anterior descending artery in mice, was associated with reduced infarct size, improved left ventricular function and decreased number of apoptotic cardiac nuclei compared with vehicle administration. The authors propose that activation of FLT3 signaling may serve as an internal, antiapoptotic, and protective system in the heart that may be particularly relevant in the setting of oxidative stress and myocardial injury. They also speculate that inhibition of FLT3 signaling, such as caused by the KIs, may result in a loss of this critical cytoprotection and lead to cardiomyocyte death.
FLT3 and FL are well-known targets in the armamentarium of anticancer therapeutics. The activating mutation in this tyrosine kinase receptor can be detected in up to 30% of acute myeloid leukemias and is associated with a distinctly poor clinical outcome for patients (2). Since the 1996 discovery of the importance of FLT3 mutation in leukemogenesis, many small molecules have been tested in an attempt to inhibit FLT3 signaling (3). Some of the KIs in currently open clinical trials in patients with malignancies carrying mutated FLT3, include crenolanib, PKC412 (midostaurin), CEP-701 (lestaurtinib), and AC220 (quizartinib), as well as more widely used multitargeted tyrosine KIs sunitinib and sorafenib. Both sunitinib and sorafenib have been associated with cardiac adverse effects ranging from hypertension and acute coronary syndrome to left ventricular dysfunction and heart failure. It is important to note that these 2 KIs, in addition to FLT3, inhibit a large a number of distinct kinases and recent studies have suggested that their inhibition of the vascular endothelial growth factor–signaling pathway may be the key underlying mechanism leading to cardiotoxic phenomena (4). However, little is known regarding if and what role different KIs' targets may have in cardiac cellular homeostasis.
Kinases have been a long-time “darling” of cancer researchers. The clinical success of imatinib, the first approved inhibitor of BCR-Abl kinase mutated in chronic myeloid leukemia, was followed by an explosion of oncological agents designed to inhibit different, frequently more ubiquitously expressed kinases (5). With the growth of several kinase-targeted oncological therapies, unexpected and serious cardiotoxic events, including left ventricular dysfunction and heart failure, have been observed (6). These reports rapidly highlighted our limited understanding of the heart kinome and the urgent need for investigations of the vulnerability of the heart in the setting of kinase-targeted cancer treatment.
How do the new findings by Pfister et al. (1) translate into clinical questions of cardio-oncology? The first and most obvious question is the concern regarding potential cardiotoxicity of FLT3-targeted cancer therapeutics. If FLT3 activation is beneficial and important for cardiomyocyte survival, then blockade of this signaling pathway may lead to cardiomyocyte injury and death, resulting in clinical cardiac dysfunction. The murine model of left anterior descending artery ligation, used in this study, does not help us answer the question if clinical comorbidities, such as hypertension, or previous myocardial infarction (frequently encountered in patients with cancer) may represent conditions in which FLT3 activation of the survival chain may be critically important. Identifying which patients may be at increased risk for cardiotoxicity with FLT3-targeted therapeutics remains a question for future studies. For the interested reader, the recent state-of-the-art paper by Lal et al. (7) summarizes the need for improved pre-clinical models and outlines complementary approaches that may allow us to predict risk of cardiotoxicity related to the use of molecularly targeted cancer therapy.
Second, a frequent clinical cardio-oncology question is which specific KI or a combination of KIs with or without other cancer therapies may result in clinical cardiotoxicity. Pfister et al. (1) did not test the effects of KIs and inhibition of endogenous FLT3 signaling in their animal model. Thus, the relevance of these findings for clinically approved or investigated FLT3-targeting cancer therapeutics need further study. By providing new evidence that FLT3 inhibition may lead to cardiac injury, this study builds a strong rationale for investigation and monitoring of cardiac function in animal models as well as in patients with cancer receiving KIs that target FLT3 pathways.
An important technical limitation of this study (1) is that exogenous FL may not accurately reflect the role of endogenous FLT3 signaling in the heart. Animal models with cardiomyocyte-targeted deletion or inhibition of FLT3 and its downstream mediators will be needed to confirm the proposed role of FLT3 signaling within the heart kinome. This approach has been successfully used in studying the role of other cancer treatment-targeted kinases in the heart (4) and has opened an important area of research that continues to grow.
On the flip side of the coin is the perspective of use of FLT3 as a potential therapeutic target in cardiac ischemia. Pfister et al. (1) demonstrate beneficial effects of FLT3 signaling in the setting of increased myocardial stress, thus providing a rationale for investigating activation of FLT3 in the treatment of heart disease. The recent past provides an exciting example of how to pursue this research question: cardiotoxicity seen in patients with breast cancer treated with the ErbB2 (HER2) receptor-targeted monoclonal antibody trastuzumab has led to the discovery of critical HER2 signaling in the heart, thus forming a foundation for clinical investigations of the HER2-receptor agonist neuregulin (8). Today, neuregulin is being tested in Phase III clinical trials for the treatment of chronic heart failure and exemplifies a model of successful reverse translation research in cardio-oncology (9).
The study by Pfister et al. (1) is the first to show that FLT3 activation may have an important role in regulating and promoting cardiac cell survival. At present, it is unclear whether and in what clinical setting the inhibition of this kinase by novel FLT3-targeted oncological therapies may lead to cardiac injury and cardiotoxicity. We await future studies to build on the initial observations by Pfister et al. and to discover how targeting FLT3 kinase can hurt or help the heart kinome.
↵∗ Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology.
Dr. Barac is supported by the Georgetown–Howard Universities Center for Clinical & Translational Science Post-doctoral KL2 Award (5KL2TR000102-04); has received research funding and honoraria for lectures from Genentech Inc.; and has received consultancy fees from Cell Therapeutics, Inc.
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