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Promising Therapy in Lung Cancer: Spotlight on Aurora Kinases

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Promising Therapy in Lung Cancer: Spotlight on Aurora Kinases cancers Review Promising Therapy in Lung Cancer: Spotlight on Aurora Kinases Domenico Galetta 1,* and Lourdes Cortes-Dericks 2 1 Division of Thoracic Surgery, European Institute of Oncology, IRCCS, 20141 Milan, Italy 2 Department of Biology, University of Hamburg, 20146 Hamburg, Germany; [email protected] * Correspondence: [email protected] Received: 4 September 2020; Accepted: 12 November 2020; Published: 14 November 2020 Simple Summary: Lung cancer has remained one of the major causes of death worldwide. Thus, a more effective treatment approach is essential, such as the inhibition of specific cancer-promoting molecules. Aurora kinases regulate the process of mitosis—a process of cell division that is necessary for normal cell proliferation. Dysfunction of these kinases can contribute to cancer formation. In this review, we present studies indicating the implication of Aurora kinases in tumor formation, drug resistance, and disease prognosis. The effectivity of using Aurora kinase inhibitors in the pre-clinical and clinical investigations has proven their therapeutic potential in the setting of lung cancer. This work may provide further information to broaden the development of anticancer drugs and, thus, improve the conventional lung cancer management. Abstract: Despite tremendous efforts to improve the treatment of lung cancer, prognosis still remains poor; hence, the search for efficacious therapeutic option remains a prime concern in lung cancer research. Cell cycle regulation including mitosis has emerged as an important target for cancer management. Novel pharmacological agents blocking the activities of regulatory molecules that control the functional aspects of mitosis such as Aurora kinases are now being investigated. The Aurora kinases, Aurora-A (AURKA), and Aurora B (AURKB) are overexpressed in many tumor entities such as lung cancer that correlate with poor survival, whereby their inhibition, in most cases, enhances the efficacy of chemo-and radiotherapies, indicating their implication in cancer therapy. The current knowledge on Aurora kinase inhibitors has increasingly shown high potential in ensuing targeted therapies in lung malignancies. In this review, we will briefly describe the biology of Aurora kinases, highlight their oncogenic roles in the pre-clinical and clinical studies in lung cancer and, finally, address the challenges and potentials of Aurora kinases to improve the therapy of this malignancy. Keywords: Aurora kinases; AURKA; AURKB; lung cancer; lung cancer therapy 1. Background Lung cancer remains the most commonly occurring cancer attributed to the leading cause of cancer-related deaths globally. Non-small cell lung cancer (NSCLC) comprises 85% to 90% of lung cancers while small cell lung cancer (SCLC) represents 10–15% [1–3]. Survival varies according to the clinical stage ranging from 92% for earliest stage to 0% for advanced stage, respectively [4]. While surgery is the treatment of choice for early stages NSCLC, chemo-radiotherapy has been the therapy of choice for the advanced stages for many years [5]. Nowadays, in advanced non-small cell lung cancer, molecular targeted therapy is the standard first-line treatment for patients with identified driver mutations; on the other hand, chemotherapy (platinum-based) is the standard treatment for patients without driver mutation or those with unknown mutation status [6–9]. Moreover, immunotherapy has been now established as one of the most promising therapeutic options [10]. Cancers 2020, 12, 3371; doi:10.3390/cancers12113371 www.mdpi.com/journal/cancers CancersCancersCancers 2020 2020, 202012,, 12x, FOR12, x, FORx PEERFOR PEER PEER REVIEW REVIEW REVIEW 2 of2 17of2 of17 17 Cancers 2020, 12, 3371 2 of 15 immunotherapyimmunotherapyimmunotherapy has has beenhas been been now now now established established established as asone as one ofone ofthe of the mostthe most most promising promising promising therapeutic therapeutic therapeutic options options options [10]. [10]. [10]. At At At thisthis time,this time, time, chemo- chemo- chemo- and and andradiotherapies radiotherapies radiotherapies are are no are no longer no longer longer the the best the best bestoption option option for for this for this diseasethis disease disease [11] [11] [11]so sothat so that thatfurther further further At this time, chemo- and radiotherapies are no longer the best option for this disease [11] so that further investigationinvestigationinvestigation of ofthe of the molecularthe molecular molecular processes processes processes surrounding surrounding surrounding the the oncogenesisthe oncogenesis oncogenesis of ofthis of this thismalignancy malignancy malignancy warrants warrants warrants investigation of the molecular processes surrounding the oncogenesis of this malignancy warrants the thethe developmentthe development development of ofmore of more more effective effective effective pharmacological pharmacological pharmacological agents. agents. agents. development of more effective pharmacological agents. TheThe Thenormal normal normal growth growth growth and and anddevelopment development development of ofa ofcell a cella stricell strictly strictly dependsctly depends depends on on its on itsability its ability ability to todivide to divide divide regularly regularly regularly The normal growth and development of a cell strictly depends on its ability to divide regularly duringduringduring the the various the various various stages stages stages of ofcell of cell division.cell division. division. This This This pr ocesspr processocess is regulatedis isregulated regulated by by several by several several mitotic mitotic mitotic kinases kinases kinases (serine- (serine- (serine- during the various stages of cell division. This process is regulated by several mitotic kinases threoninethreoninethreonine kinases) kinases) kinases) which which which include include include polo-like polo-like polo-like kinases, kinases, kinases, cyclin cyclin cyclin dependent dependent dependent kinase kinase kinase 1 (CDK1),1 1(CDK1), (CDK1), large large large tumor tumor tumor (serine-threonine kinases) which include polo-like kinases, cyclin dependent kinase 1 (CDK1), suppressorsuppressorsuppressor 1 (LATS1)-related 1 (LATS1)-related1 (LATS1)-related kinases, kinases, kinases, never never never in inmito in mito mitosissis (NIMA)sis (NIMA) (NIMA) -related -related -related kinases, kinases, kinases, and and andAurora Aurora Aurora kinases kinases kinases large tumor suppressor 1 (LATS1)-related kinases, never in mitosis (NIMA) -related kinases, and Aurora executeexecuteexecute critical critical critical roles roles roles in indifferent in different different stages stages stages of ofcell of cell divisioncell division division [12]. [12]. [12]. kinases execute critical roles in different stages of cell division [12]. TheThe TheAurora Aurora Aurora kinases kinases kinases consisting consisting consisting of ofthree of three three members members members termed termed termed Aurora-A Aurora-A Aurora-A (AURKA), (AURKA), (AURKA), -B -B(AURKB), -B (AURKB), (AURKB), and and and The Aurora kinases consisting of three members termed Aurora-A (AURKA), -B (AURKB), and –C –C–C (AURKC)–C (AURKC) (AURKC) are are complementaryare complementary complementary enzymes enzymes enzymes that that thatmodu modu modulatelate latemultiple multiple multiple mitotic mitotic mitotic events. events. events. These These These mitotic mitotic mitotic (AURKC) are complementary enzymes that modulate multiple mitotic events. These mitotic kinases kinaseskinaseskinases are are expressedare expressed expressed in ina in cella acell cycle-dependentcell cycle-dependent cycle-dependent ma manner, manner,nner, most most most of ofwhich of which which are are activatedare activated activated in inthe in the G2/Mthe G2/M G2/M are expressed in a cell cycle-dependent manner, most of which are activated in the G2/M phase being phasephasephase being being being involved involved involved in inmitotic in mitotic mitotic chromosomal chromosomal chromosomal segregation segregation segregation [13,14]. [13,14]. [13,14]. These These These kinases kinases kinases bind bind bind to toprotein to protein protein involved in mitotic chromosomal segregation [13,14]. These kinases bind to protein partners to be partnerspartnerspartners to tobe to belocally be locally locally functional, functional, functional, that that thatare are tightly are tightly tightly regulated regulated regulated in ina temporalin a temporala temporal and and andspatial spatial spatial manner. manner. manner. AURKA AURKA AURKA locally functional, that are tightly regulated in a temporal and spatial manner. AURKA and AURKB andand andAURKB AURKB AURKB are are theare the onlythe only only ones ones ones of ofthe of the Aurorathe Aurora Aurora kinase kinase kinase family family family to tobe to beexpressed be expressed expressed at atdetectable at detectable detectable levels levels levels in in in are the only ones of the Aurora kinase family to be expressed at detectable levels in somatic cells somaticsomaticsomatic cells cells cells during during during mitotic mitotic mitotic processes processes processes and and andtheir their their func func functiontion tionin incellular in cellular cellular processes processes processes in inthe in the developmentthe development development of of of during mitotic processes and their function in cellular processes in the development of tumorigenic tumorigenictumorigenictumorigenic phenotypes phenotypes phenotypes has
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