Alexander Schultze

Acute myeloid leukemia (AML) represents a clonal disease of hematopoietic progenitors characterized by acquired heterogenous genetic changes that alter normal mechanisms of proliferation, self-renewal, and differentiation.(1) Although 40% to 45% of patients younger than 65 years of age can be cured with current therapies, only 10% of older patients reach long-term survival.(1) Because only very few novel AML drugs were approved in the past 2 decades, there is an urgent need to identify novel targets and therapeutic strategies to treat underserved AML patients. We report here that Axl, a member of the Tyro3, Axl, Mer receptor tyrosine kinase family,(2-4) represents an independent prognostic marker and therapeutic target in AML. AML cells induce expression and secretion of the Axl ligand growth arrest-specific gene 6 (Gas6) by bone marrow-derived stromal cells (BMDSCs). Gas6 in turn mediates proliferation, survival, and chemoresistance of Axl-expressing AML cells. This Gas6-Axl paracrine axis between AML cells and BMDSCs establishes a chemoprotective tumor cell niche that can be abrogated by Axl-targeting approaches. Axl inhibition is active in FLT3-mutated and FLT3 wild-type AML, improves clinically relevant end points, and its efficacy depends on presence of Gas6 and Axl. Axl inhibition alone or in combination with chemotherapy might represent a novel therapeutic avenue for AML.

IMPORTANCE OF THE FIELD: Activation of the non-receptor tyrosine kinase focal adhesion kinase (FAK) has been implicated in progression of multiple mesenchymal and epithelial malignant tumors. FAK plays an important role in regulation of proliferation, migration and apoptosis of neoplastic cells. AREAS COVERED IN THIS REVIEW: We review the importance of FAK expression as a prognostic marker in cancer patients, discuss the available small-molecule inhibitors of FAK, summarize the available data from early-phase clinical trials with FAK inhibitors and cover the antiangiogenic properties of FAK inhibitors, as well as their potential to overcome chemoresistance. WHAT THE READER WILL GAIN: This review enables the reader to overview current knowledge about FAK inhibition in cancer therapy and its role in the clinical setting. The reader will be able to consider FAK inhibitors not only as direct antitumor but also as antineoangiogenic agents and drugs that can overcome the problem of chemoresistance. TAKE HOME MESSAGE: Emerging data from early-phase clinical trials with orally available small-molecule inhibitors of FAK are promising. There are early indicators of clinical efficacy. In the future, combination therapy with cytotoxic or antiangiogenic drugs may help to overcome chemoresistance and enhance efficacy of antivascular therapy.

While several studies have described the clinical course of patients with coronavirus disease 2019 (COVID-19), direct comparisons with patients with seasonal influenza are scarce. We compared 166 patients with COVID-19 diagnosed between February 27 and June 14, 2020, and 255 patients with seasonal influenza diagnosed during the 2017-18 season at the same hospital to describe common features and differences in clinical characteristics and course of disease. Patients with COVID-19 were younger (median age [IQR], 59 [45-71] vs 66 [52-77]; P < 0001) and had fewer comorbidities at baseline with a lower mean overall age-adjusted Charlson Comorbidity Index (mean [SD], 3.0 [2.6] vs 4.0 [2.7]; P < 0.001) than patients with seasonal influenza. COVID-19 patients had a longer duration of hospitalization (mean [SD], 25.9 days [26.6 days] vs 17.2 days [21.0 days]; P = 0.002), a more frequent need for oxygen therapy (101 [60.8%] vs 103 [40.4%]; P < 0.001) and invasive ventilation (52 [31.3%] vs 32 [12.5%]; P < 0.001) and were more frequently admitted to the intensive care unit (70 [42.2%] vs 51 [20.0%]; P < 0.001) than seasonal influenza patients. Among immunocompromised patients, those in the COVID-19 group had a higher hospital mortality compared to those in the seasonal influenza group (13 [33.3%] vs 8 [11.6%], P = 0.01). In conclusion, we show that COVID-19 patients were younger and had fewer baseline comorbidities than seasonal influenza patients but were at increased risk for severe illness. The high mortality observed in immunocompromised COVID-19 patients emphasizes the importance of protecting these patient groups from SARS-CoV-2 infection.