Ansar, Zeeshan A

moatter, tariq

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eCommons@AKUDepartment of Pathology and Laboratory Medicine Medical College, PakistanJuly 2014Tyrosine kinase inhibitors in cancer therapeutics:great expectations from small moleculesZeeshan A Ansartariq moatteraga khan university, tariq.moatter@aku.eduFollow this and additional works at: http://ecommons.aku.edu/pakistan_fhs_mc_pathol_microbiolPart of the Microbiology Commons, and the Pathology CommonsRecommended CitationAnsar, Z., moatter, t. (2014). Tyrosine kinase inhibitors in cancer therapeutics: great expectations from small molecules. JCPSP:Journal of the College of Physicians and Surgeons Pakistan, 24(7), 453-454.Available at: http://ecommons.aku.edu/pakistan_fhs_mc_pathol_microbiol/471In the last two decades, biomedical scientists havemade extraordinary efforts to unravel molecularintricacies underlying carcinogenesis, thus providing astrong foundation for the development of targetedcancer therapies. Application of latest moleculartechnologies have transformed our understanding ofcancer pathogenesis and mechanisms involved inneoplastic transformation.1 Cancer, as known today,is a disease that has its origin embedded in thealteration of specific genes. This hypothesis was heldtrue because several “cancer genes” have beendiscovered and characterized using high throughputmolecular technologies.2 Moreover, the completion ofhuman genome sequencing has placed a majormilestone on this path and as was anticipated in theinitial phase of the genome project, its completion hasled to significant advancements in our understanding ofcancer biology.Over the last few decades, the identification andcharacterization of the genetic changes in malignanttransformation have progressed rapidly. On the otherhand, failure of response to therapy has beenprogressively detected; these failures could be due todrug intolerance, lethal toxicities, insensitivity of targetreceptors and genetic changes or alteration in cellsignaling pathways.Cell surface receptors play crucial role in cancerbiogenesis, especially those receptors that encodefor enzymatic activities, such as tyrosine kinases,commonly known as receptor tyrosine kinases (RTKs).These are membrane-spanning cell proteins that playcritical role in transduction of extracellular signals tocytoplasm.3 There are approximately sixty RTKs, whichare divided into twenty sub-families as defined by theirligands. Among these receptors three features includingimmunoglobulin like sequence having amino terminalextracellular domain, lipophilic transmembrane segmentand an intracellular carboxyl terminal domain whichcontain tyrosine kinase catalytic site are foundcommon.4The RTKs are activated through binding with theirligands, hormones, peptide or growth factors and triggera cascade of signaling molecules subsequently leadingto transcription of genes, which regulate cell growth,proliferation, differentiation, migration and apoptosis. Inaddition, RTKs can also become activated by somaticmutations, which are identified as a commonmechanism of carcinogenesis, whereby they play animportant role in the modulation of growth factorssignaling under pathological conditions. Activated formscan cause increased tumor cell proliferation, growthinduce anti-apoptotic effects and promote angiogenesis.Therefore, detection of RTK variants in malignancies isnot only useful for the diagnosis but also becomeshelpful in their treatment, as specific markers of targetedtherapies.2In cancer therapy, during the last decade, a majordevelopment was the advent of Tyrosine KinaseInhibitors (TKI), these small molecules inhibit patho-logically induced activation of RTKs. Till date, severalRTKs can be targeted by small molecule inhibitors, andclinical evidence indicates that tumors carryingmutations involving RTK genes are particularlysusceptible to such inhibitors, most probably becauseof tumors becoming “addicted'' to specific kinasepathways. The advantages of TKI over conventionalchemotherapy are numerous; such as this treatment isspecific for cancer cells and it is less toxic and it can beutilized at any age and every stage of the disease withminimal harm to body's physiological functions. TKIshave been approved for several malignancies in bothhematolymphoid and solid tumor groups.1The first successfully used TKI, Imatinib Mesylate(Gleevec), was very effective in treating Chronic MyeloidLeukemia (CML). This success led to an acceleratedapproval of this drug in 2001. Currently, the predictedsurvival time of CML patients has improved from 15months before Imatinib to a projected 15 years after thelatter's introduction.5 With the passage of time, the list ofTKIs have expanded as well as their application invarious cancers particularly lung cancer, breast cancer,gastrointestinal stromal tumor, and female genitaltumors.One of the disadvantage of this biological treatment,which by definition is non-cytotoxic and can thus bechronically administrated, is the development ofresistance. During the course of treatment, response toJournal of the College of Physicians and Surgeons Pakistan 2014, Vol. 24 (7): 453-454 453EDITORIALTyrosine Kinase Inhibitors in Cancer Therapeutics: Great Expectations from Small MoleculesZeeshan A. Ansar and Tariq MoatterDepartment of Pathology and Microbiology, The Aga KhanUniversity Hospital, Karachi.Correspondence: Tariq Moatter, PhD, Molecular Pathology,Department of Pathology and Microbiology, The Aga KhanUniversity Hospital, Stadium Road, Karachi-74800.E-mail: tariq.moatter@aku.eduReceived: July 04, 2013;   Accepted: March 15, 2014.TKI is generally slow, which could be due to extrinsicmechanisms involving metabolism of drug, bioavail-ability or systemic deterioration due to progressiveillness. In addition, intrinsic factors can also have majorimpact on drug response, like acquired mutationsdeveloped during the course of therapy seen in CML,lung tumors, breast tumors, hepatic and renal cancers.In a tumor where a single dominant oncogene, such asthe RTK, is activated by mutations; acquired resistanceis the consequence of secondary mutations generallyaffecting the kinase domain of the receptors. Thisultimately results in the modification of the kinaseconformation, which becomes no longer compatible withthe TKI-binding.To overcome the failure of therapy, the initial approachincludes escalation of TKI dose, but it is usuallyassociated with side effects and intolerance. Newemerging second line TKIs are more potent, most ofthem have dual target/receptor action with high efficacy.6The combination of second line with first line TKIs wasfound significantly more effective and less toxic invarious clinical trials.6In future, prospective use of molecular modeling andsimulation for the selection of new TKIs is likely to pavethe way towards a truly personalized treatment. Theupcoming future technologies have the potential fordesigning multi-targeted therapeutic agents with theability to effectively inhibit both primary and/or expectedsecondary mutations.7 The new agents in the pipelineinclude multi-targeted TKIs and non-selective inhibitorsof tyrosine kinases. Majority of these are currently in pre-clinical workup or phase I/II trials and hopefully, theseagents will soon become available for treatment ofcancer patients as mono or combination therapies.REFERENCES1. Osmond JD, Fatih MU. Novel Bruton's tyrosine kinaseinhibitors currently in development. OncoTargets Therap 2013;6:161-17.2. Luo J, Solimini NL, Elledge S. Principles of cancer therapies:oncogene and non-oncogene addiction. Cell 2009; 136:823-37.3. Pawson T. Regulation and targets of receptor tyrosine kinases.Eur J Cancer 2002; 38:S3-S10.4. Druker BJ. Efficacy and safety of a specific inhibitor of theBCR-ABL tyrosine kinase in chronic myeloid leukemia. N EnglJ Med 2001; 344:1031-7.5. Arteaga CL. The epidermal growth factor receptor: from mutantoncogene in non-human cancers to therapeutic target inhuman neoplasia. J Clin Oncol 2001; 19:32S-40S.6. Prenen H, Guetens G, de Boeck G, Debiec-Rychter M, ManleyP, Schoffski P, et al. Cellular uptake of the tyrosine kinaseinhibitors imatinib and AMN107 in gastrointestinal stromaltumor cell lines. Pharmacology 2006; 77:11-6.7. Palassini EF, Coco P, Piovesan C, Dileo P, Bertulli R, CasaliPG, et al. Combination of PKC412 and sirolimus in ametastatic patient with PDGFRA-D842 V gastrointestinalstromal tumour (GIST). J Clin Oncol 2008; 20:21515.Zeeshan A. Ansar and Tariq Moatter454 Journal of the College of Physicians and Surgeons Pakistan 2014, Vol. 24 (7): 453-454

Tyrosine kinase inhibitors in cancer therapeutics: great expectations from small molecules

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Tyrosine kinase inhibitors in cancer therapeutics: great expectations from small molecules

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