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Dasatinib is a multitargeted kinase inhibitor used for treatment of chronic myeloid leukemia and acute lymphoblastic leukemia. Unfortunately, treatment of cancer patients with some kinase inhibitors has been associated with cardiotoxicity. Cancer treatment with dasatinib has been reported to be associated with cardiotoxic side effects such as left ventricular dysfunction, heart failure, pericardial effusion and pulmonary hypertension. Here we aimed to investigate the molecular mechanisms underlying the cardiotoxicity of dasatinib. We found that among the resident cardiac cell types, cardiomyocytes were most sensitive to dasatinib-induced cell death. Exposure of cardiomyocytes to dasatinib attenuated the activity of extracellular signal-regulated kinase (ERK), which is a downstream target of dasatinib target kinase c-Src. Similar to dasatinib, c-Src depletion in cardiomyocytes compromised cardiomyocyte viability. Overexpression of dasatinib-resistant mutant of c-Src rescued the toxicity of dasatinib on cardiomyocytes, whereas forced expression of wild type c-Src did not have protective effect. Collectively, our results show that c-Src is a key target of dasatinib mediating the toxicity of dasatinib to cardiomyocytes. These findings may influence future drug design and suggest closer monitoring of patients treated with agents targeting c-Src for possible adverse cardiac effects.

Since 2006, the European conditional marketing authorization (CMA) aims to facilitate timely patient access to medicinal products for which there is an unmet medical need by accepting less comprehensive data than normally required. The granting of CMA requires a positive benefit–risk balance, unmet medical needs to be fulfilled, likely submission of comprehensive data postauthorization, and the benefit of immediate availability to outweigh the risks of data noncomprehensiveness. Since its first use, more than half of all CMAs represent (hemato-)oncology indications. Therefore, we aimed to investigate the conditions in which CMA has been applied for anticancer medicinal products and whether they have changed over time. We retrospectively assessed the European public assessment reports of the 30 anticancer medicinal products granted CMA in 2006–2020 (51% of all 59 CMAs). Comparison of 2006–2013 to 2014–2020 highlighted increased proportions of proactively requested CMAs (+40%), medicinal products that addressed unmet medical needs by providing a major therapeutic advantage over authorized treatments (+38%), and orphan designated indications (+32%). In contrast, it showed decreased proportions of medicinal products for which a scientific advisory group was consulted (−55%) and phase III randomized controlled trial data were available (−38%). This suggests that applicants and the European Medicines Agency have learned how to use the CMA as a regulatory tool, among others, through better planning and proactive interaction. However, the increasing number of granted CMAs complicates the establishment of unmet medical need and the benefit–risk balance, especially in crowded indications and when only phase II uncontrolled trials are available.

Tiivistelmä Virtsarakon syöpä on toiseksi yleisin urologinen syöpä. Sen ensioireena on useimmiten makroskooppinen verivirtsaisuus, jonka alkuperän selvittämiseksi voidaan tehdä virtsarakon tähystys ja radiologiset lisätutkimukset. Kasvaimen höyläyksellä saadaan histologinen varmistus kasvaimen erilaistumisasteesta ja invaasion syvyydestä. Hoito määräytyy taudin patologisten tekijöiden sekä levinneisyyden perusteella. Ei-lihasinvasiivisen rakkosyövän uusiutumista ja etenemistä pyritään estämään rakkoinstillaatioilla, mikäli tauti on huonosti erilaistunut, kasvaa invasiivisesti lamina propriaan tai uusiutuu toistuvasti, mutta lihakseen edenneen syövän ensisijainen hoito on edelleen radikaalikirurgia. Säde- ja kemosädehoito ovat vaihtoehtoina leikkaukseen soveltumattomille potilaille. Etäpesäkkeistä tautia hoidetaan solunsalpaajilla ja immunologisella lääkehoidolla.

The traditional drug development paradigm, consisting of sequential phases and randomized studies, has been challenged in oncology and hemato‐oncology. In the regulatory context, a number of new products have been authorized based on nonrandomized efficacy and safety data. We retrospectively analyzed the European public assessment reports for anticancer treatments authorized between 2010 and 2019 to describe the data behind such approvals. Twenty‐two initial marketing authorizations, mainly conditional, were identified. Fifty percent of the products had an orphan indication, and 77% had received previous scientific advice. Conclusions of clinical benefit were based on tumor responses, ranging between 15.8 and 88%. Our data shows that single‐arm clinical studies leading to positive regulatory outcomes share common methodological approaches and end points, mostly comparing the overall response rate with a fixed success threshold as the primary analysis. The clinical indications in these approvals are clustered in late‐line settings, hematological malignancies, and lung cancer. Our findings underline the need to reflect on the current practice, the methodological aspects, and end points in single‐arm studies, and develop specific regulatory guidance on nonrandomized and novel study designs.

Background: Small molecule kinase inhibitors (KIs) are a class of agents currently used for treatment of various cancers. Unfortunately, treatment of cancer patients with some of the KIs is associated with cardiotoxicity, and there is an unmet need for methods to predict their cardiotoxicity. Here, we utilized a novel computational method to identify protein kinases crucial for cardiomyocyte viability. Methods and Results: One hundred forty KIs were screened for their toxicity in cultured neonatal cardiomyocytes. The kinase targets of KIs were determined based on integrated data from binding assays. The key kinases mediating the toxicity of KIs to cardiomyocytes were identified by using a novel machine learning method for target deconvolution that combines the information from the toxicity screen and from the kinase profiling assays. The top kinases identified by the model were phosphoinositide 3‐kinase catalytic subunit alpha, mammalian target of rapamycin, and insulin‐like growth factor 1 receptor. Knockdown of the individual kinases in cardiomyocytes confirmed their role in regulating cardiomyocyte viability. Conclusions: Combining the data from analysis of KI toxicity on cardiomyocytes and KI target profiling provides a novel method to predict cardiomyocyte toxicity of KIs.