Perencat Kinase Molekul Kecil Untuk Terapi Sasaran Kanser
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Ditulis oleh: Dr. Lee Pey Yee
Tarikh: 27 Jun 2022
Kinase adalah enzim yang memangkinkan pemindahan fosfat daripada ATP kepada spesifik substrat selular. Proses ini dikenali sebagai fosforilasi dan mengawal laluan isyarat intraselular yang bertanggungjawab untuk mengawal selia pelbagai proses biologi, seperti percambahan sel, kemandirian, pembezaan dan metabolisme. Dalam eukariota, tapak fosforilasi utama kinase protein ialah serin (Ser), threonine (Thr), dan tyrosine (Tyr), manakala dalam prokariot, fosforilasi utama berlaku pada asid aspartik (Asp), asid glutamat (Glu), dan histidine (His) [1]. Asid amino lain yang juga boleh difosforilasi termasuk arginin (Arg), lisin (Lys), dan sistein (Cys) [2]. Akibat mutasi somatik, laluan isyarat yang dimediasi oleh kinase protein kerap terganggu dalam penyakit manusia. Kebanyakan onkogen dominan yang telah ditemui melibatkan mutasi dan/atau pengekspresan kinase protein yang tinggi dalam penyakit kanser [3]. Memandangkan genom manusia mengekodkan 538 kinase protein dan kebanyakan kinase ini terlibat dengan perkembangan penyakit manusia terutamanya kanser, bidang penyelidikan ini mempunyai potensi besar untuk kemajuan terapi masa depan.
Kinase telah menarik minat yang besar sebagai sasaran yang berpotensi untuk rawatan terapeutik. Terdapat dua strategi utama yang digunakan untuk terapi sasaran kinase iaitu perencat kinase molekul kecil (KIs) dan antibodi monoklonal (mAbs). KIs molekul kecil boleh dikategorikan secara amnya kepada tujuh jenis berdasarkan mekanisme tindakan dan mod pengikatan sasaran (Jadual 1). Perencat jenis I mengikat tapak pemangkin kinase sasaran dalam konformasi aktif, di mana motif gelung pengaktifan Asp-Phe-Gly (DFG) yang berorientasikan ke bahagian dalam kinase dan diselaraskan dengan tapak pengikat ATP (konformasi masuk DFG) [4]. Subjenis perencat jenis I, jenis 1½ mengikat ke tapak ATP dan memanjang ke dalam poket belakang (konformasi masuk DFG dan C-helix keluar) [5]. Berbeza dengan perencat jenis I, perencat jenis II mengikat kepada kinase sasaran dalam konformasi tidak aktif, di mana motif DFG diarahkan jauh dari tapak pengikat ATP (konformasi keluar DFG). Perencat jenis III mengikat jauh dari tapak pengikat ATP pemangkin di mana ia memodulasi aktiviti kinase dengan cara alosterik [6]. Ia boleh dikelaskan lagi kepada dua subjenis: (i) perencat jenis IIIA yang mengikat pada tapak dalam poket pengikat adenin di sebelah tapak pengikatan ATP; dan (ii) perencat jenis IIIB yang mengikat di tempat lain. Perencat jenis IV atau perencat terarah substrat ialah perencat alosterik yang menyasarkan kawasan di luar tapak pengikat ATP tetapi tidak bertindih dengan perencat jenis III [7]. Perencat jenis V adalah perencat bivalen yang mengikat secara tidak boleh balik kepada tapak kinase aktif dan motif peptida yang mewakili substrat yang disasarkan oleh kinase [8]. Perencat jenis VI mengikat secara kovalen kepada sasaran kinase mereka melalui interaksi kumpulan elektrofilik reaktif perencat dengan terutamanya sistein nukleofilik [9]. Perencat jenis VII ditakrifkan sebagai perencat alosterik bukan klasik yang menyasarkan domain ekstraselular kinase tirosin reseptor.
Jadual 1. Ciri-ciri pelbagai jenis perencat kinase
Rajah 1. Perencat kinase molekul kecil yang diluluskan oleh FDA untuk rawatan kanser dan bukan kanser.
Sehingga kini, Pentadbiran Makanan dan Dadah (FDA) telah meluluskan lebih daripada 70 KI molekul kecil di Amerika Syarikat (Rajah 1) [10], dan banyak lagi ubat yang masih dalam penilaian. Dalam konteks Malaysia, akses dan liputan rawatan untuk beberapa terapi sasaran adalah agak baik. Kanser darah seperti leukemia dan limfoma mempunyai liputan rawatan yang agak tinggi iaitu masing-masing kira-kira 96% dan 75% (Rajah 2). Walau bagaimanapun, liputan rawatan terapi sasaran lain untuk tumor pepejal seperti kanser paru-paru, payudara, buah pinggang, ovari dan kolon adalah rendah, iaitu antara 7 hingga 24%. Data semasa telah menunjukan bahawa KI mempunyai permintaan tinggi dalam penyelidikan dadah, terutamanya untuk rawatan kanser. Imatinib (Gleevec) adalah KI pertama yang telah mendapat kelulusan untuk terapi manusia, dan menjadi perintis untuk pembangunan ubat sasaran kinase seterusnya. Pengenalan imatinib ke dalam amalan klinikal pada tahun 2001 telah menukarkan leukemia myeloid kronik (CML) daripada penyakit yang berpotensi membawa maut kepada keadaan yang boleh diuruskan dan telah meningkatkan prognosis pesakit secara dramatik [11]. Imatinib ialah KI generasi pertama yang menyasarkan kinase gabungan Bcr-Abl yang memacu CML. Walau bagaimanapun, kemunculan mutasi dalam domain kinase BCR-ABL telah mengakibatkan perkembangan rintangan terhadap terapi imatinib. Bcr-Abl KI generasi kedua termasuk dasatinib, bosutinib dan nilotinib kemudiannya dibangunkan untuk pesakit dengan rintangan imatinib dan aktif terhadap beberapa jenis mutan Bcr-Abl yang tidak sensitif imatinib kecuali mutasi T315I [12]. Bcr-Abl KI ponatinib generasi ketiga berkesan terhadap spektrum mutan yang luas termasuk mutasi T315I [13].
Rajah 2. Liputan terapi sasaran untuk rawatan kanser di Malaysia.
Epidermal growth factor receptor (EGFR) ialah contoh lain kinase pemacu onkogenik yang telah disasarkan untuk terapi. Disregulasi dalam isyarat yang disebabkan oleh perubahan dalam EGFR dan komponen lain yang berkait rapat, seperti ErbB2 atau HER2 telah dikaitkan dengan perkembangan kanser [14]. Gefitinib dan erlotinib adalah EGFR KI generasi pertama yang diluluskan untuk merawat kanser paru-paru bukan sel kecil (NSCLC) mutan EGFR [15]. KI EGFR generasi kedua seperti afatinib dan dacomitinib adalah perencat pengikat tidak boleh balik yang lebih kuat daripada KI EGFR generasi pertama terhadap EGFR dan EGFR jenis liar dengan Del19 atau L858R serta memaparkan aktiviti yang luas terhadap pelbagai reseptor ErbB termasuk EGFR, HER2, dan HER4 [16,17]. Namun begitu, mutasi yang menyebabkan perubahan konformasi pada reseptor dan pengaktifan laluan isyarat pampasan telah mengakibatkan penentangan terhadap perencat generasi pertama dan kedua. EGFR KI generasi ketiga seperti osimertinib adalah perencat pengikat tidak boleh balik untuk kanser dengan rintangan yang diperoleh akibat mutasi T790M sekunder [18].
Komponen laluan mitogen-activated protein kinase (MAPK) adalah satu lagi sasaran terapeutik yang penting [19]. Beberapa KI, terutamanya vemurafenib, dabrafenib, dan encorafenib menyasarkan BRAF, gen yang sering bermutasi dalam laluan MAPK [20]. Ubat tersebut mempamerkan aktiviti perencatan yang kuat terhadap mutan BRAF V600E. Selain itu, vemurafenib dan dabrafenib juga berkesan terhadap mutan BRAF V600D dan V600R [21,22], manakala encorafenib boleh menghalang mutan V600K dan BRAF jenis liar [23]. Perencat BRAF juga boleh digabungkan dengan perencat MEK seperti trametinib, cobimetinib, binimetinib, dan selumetinib untuk perencatan laluan MAPK yang berkesan dan berterusan [24]. Kinase sasaran KI lain yang diluluskan oleh FDA adalah cyclin-dependent kinase (CDK), hepatocyte growth factor (HGF, juga dikenali sebagai kinase tyrosine-protein MET), platelet-derived growth factor beta-receptor (PDGFR), fibroblast growth factor receptor (FGFR), Janus kinase (JAK), Bruton’s tyrosine kinase (BTK), mechanistic target of rapamycin (mTOR), colony stimulating factor 1 receptor (CSF1R), Rearranged during Transfection (RET), anaplastic lymphoma kinase (ALK), tropomyosin receptor kinase (TRK) dan spleen tyrosine kinase (Syk).
Walaupun perencat kinase mewakili satu inovasi dalam rawatan kanser, ia tidak dapat memberi manfaat kepada setiap pesakit. Mutasi yang mengubah urutan asid amino, konformasi, atau tahap ekspresi kinase telah digunakan oleh sel tumor sebagai mekanisme untuk mengelak tindakan ubat [25]. Ini menghalang ubat molekul kecil daripada mengakses tapak pengikat dan mengganggu isyarat protein, mengakibatkan kekurangan aktiviti perencat kinase dan perkembangan rintangan ubat. Sebaliknya, pencarian pemain molekul utama yang boleh diterjemahkan ke dalam terapi dunia nyata masih mencabar. Kanser dicirikan oleh landskap molekul yang kompleks, dan lebih berkemungkinan disebabkan oleh pengubahan lebih daripada satu kinase; oleh itu, pencirian hubungan penuh penyakit-kinase adalah penting. Oleh itu, penyelidikan lanjut masih diperlukan untuk mengenal pasti kinase pemacu baharu yang berpotensi dan biomarker ramalan. Selain itu, landskap semasa perencat kinase juga menunjukkan keperluan untuk meneroka laluan baharu dan petunjuk baharu untuk mencapai potensi penuh mereka bukan sahaja untuk kanser, tetapi juga untuk penyakit lain.
Rujukan
[1] Adam K & Hunter T (2018) Histidine kinases and the missing phosphoproteome from prokaryotes to eukaryotes. Lab Investig 98, 233–247.
[2] Cieśla J, Fraczyk T & Rode W (2011) Phosphorylation of basic amino acid residues in proteins: Important but easily missed. Acta Biochim Pol 58, 137–148.
[3] Blume-Jensen P & Hunter T (2001) Oncogenic kinase signalling. Nature 411, 355–365.
[4] Dar AC & Shokat KM (2011) The evolution of protein kinase inhibitors from antagonists to agonists of cellular signaling. Annu Rev Biochem 80, 769–795
[5] Zuccotto F, Ardini E, Casale E & Angiolini M (2009) Through the “gatekeeper door”: exploiting the active kinase conformation. J Med Chem 53, 2681–2694.
[6] Roskoski R (2016) Classification of small molecule protein kinase inhibitors based upon the structures of their drug-enzyme complexes. Pharmacol Res 103, 26–48.
[7] Gavrin LK & Saiah E (2013) Approaches to discover non-ATP site kinase inhibitors. Med Chem Comm 4, 41–51.
[8] Lamba V & Ghosh I (2012) New directions in targeting protein kinases: focusing upon true allosteric and bivalent inhibitors. Curr Pharm Des 18, 2936–2945.
[9] Martinez R III, Defnet A & Shapiro P (2020) Avoiding or Co-Opting ATP Inhibition: Overview of Type III, IV, V, and VI Kinase Inhibitors. Next Generation Kinase Inhibitors 29–59.
[10] (http://www.brimr.org/PKI/PKIs.htm),
[11] Druker B, Sawyers C, Kantarjian H, Resta D, Reese S, Ford J, Capdeville R & Talpaz M (2001) Activity of a specific inhibitor of the BCR-ABL tyrosine kinase in the blast crisis of chronic myeloid leukemia and acute lymphoblastic leukemia with the Philadelphia chromosome. N Engl J Med 344, 1038–1042.
[12] Hochhaus A, Saussele S, Rosti G, Mahon F-X, Janssen J, Hjorth-Hansen H & Al E (2017) Chronic myeloid leukaemia: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 28(suppl_4, iv41–51.
[13] O’Hare T, Shakespeare W, Zhu X, Eide C, Rivera V, Wang F, Adrian L, Zhou T, Huang W, Xu Q, Metcalf C, Tyner J, Loriaux M, Corbin A, Wardwell S, Ning Y, Keats J, Wang Y, Sundaramoorthi R, Thomas M, Zhou D, Snodgrass J, Commodore L, Sawyer T, Dalgarno D, Deininger M, Druker B & Clackson T (2009) AP24534, a pan-BCR-ABL inhibitor for chronic myeloid leukemia, potently inhibits the T315I mutant and overcomes mutation-based resistance. Cancer Cell 16, 401–412.
[14] Roskoski Jr R (2014) The ErbB/HER family of protein-tyrosine kinases and cancer. Pharmacol Res 79, 34–74.
[15] Riely G, Politi K, Miller V & Pao W (2006) Update on epidermal growth factor receptor mutations in non-small cell lung cancer. Clin Cancer Res 12, 7232–7241.
[16] Hirsh V (2015) Next-generation covalent irreversible kinase inhibitors in NSCLC: focus on afatinib. BioDrugs 29, 167–183.
[17] Ou S & Soo R (2015) Dacomitinib in lung cancer: a “lost generation” EGFR tyrosine-kinase inhibitor from a bygone era? Drug Des Devel Ther 9, 5641–5653.
[18] Finlay M, Anderton M, Ashton S & Al E (2014) Discovery of a potent and selective EGFR inhibitor (AZD9291) of both sensitizing and T790M resistance mutations that spares the wild type form of the receptor. J Med Chem 57, 8249–8267.
[19] Burotto M, Chiou V, Lee J & Kohn E (2014) The MAPK pathway across different malignancies: a new perspective. Cancer 120, 3446–3456.
[20] Savoia P, Fava P, Casoni F & Cremona O (2019) Targeting the ERK signaling pathway in melanoma. Int J Mol Sci 20, 1483
[21] Yang H, Higgins B, Kolinsky K, Packman K, Go Z, Iyer R, Kolis S, Zhao S, Lee R, Grippo J & Al. E (2010) RG7204 (PLX4032), a selective BRAFV600E inhibitor, displays potent antitumor activity in preclinical melanoma models. Cancer Res 70, 5518–5527.
[22] Gentilcore G, Madonna G, Mozzillo N, Ribas A, Cossu A, Palmieri G & Ascierto P (2013) Effect of dabrafenib on melanoma cell lines harbouring the BRAF(V600D/R) mutations. BMC Cancer 13, 17.
[23] Koelblinger P, Thuerigen O & Dummer R (2018) Development of encorafenib for BRAF-mutated advanced melanoma. Curr Opin Oncol 30, 125–133.
[24] Daud A & Tsai K (2017) Management of treatment-related adverse events with agents targeting the MAPK pathway in patients with metastatic melanoma. Oncologist 22, 823–833.
[25] Lovly CM & Shaw AT (2014) Molecular pathways: resistance to kinase inhibitors and implications for therapeutic strategies. Clin Cancer Res 20, 2249-2256.
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Written by: Dr. Lee Pey Yee
Date: 27 June 2022
Kinase is an enzyme that catalyzes the transfer of a phosphate from ATP to a specific residue of cellular substrates. This process is known as phosphorylation and governs the intracellular signalling pathways that are responsible for regulating a wide range of biological processes, such as cell proliferation, survival, differentiation and metabolism. In eukaryotes, the primary phosphorylation sites of a protein kinase are serine (Ser), threonine (Thr), and tyrosine (Tyr) residues, whereas in prokaryotes, phosphorylation mainly occurs at aspartic acid (Asp), glutamic acid (Glu), and histidine (His) residues [1]. Other less common amino acid residues that can be phosphorylated include arginine (Arg), lysine (Lys), and cysteine (Cys) [2]. As a result of somatic mutations, signalling pathways that are mediated by protein kinases frequently become disrupted in human diseases. Many of the dominant oncogenes that have been discovered encode protein kinases that are known to be mutated and/or overexpressed in human malignancies [3]. Given that the human genome encodes 538 protein kinases and that many of these kinases are involved with the onset and development of human diseases, particularly cancer, this research area holds great potential for future therapy advancements.
Over the years, kinases have attracted great interest as potential targets for therapeutic intervention. The two primary strategies used for kinase-targeted therapies include small-molecule kinase inhibitors (KIs) and monoclonal antibodies (mAbs). The small-molecule KIs can be broadly categorized into seven types based on their mechanisms of action and modes of target binding (Table 1). Type I inhibitors bind to the catalytic site of a target kinase in an active conformation, whereby the conserved Asp-Phe-Gly (DFG) motif of the activation loop is oriented toward the interior of the kinase and aligned with the ATP-binding site (the DFG-in conformation) [4]. A subtype of type I inhibitor, type 1½ binds to ATP binding region and extends into the back pocket (DFG-in conformation and C-helix out) [5]. In contrast to type I inhibitors, type II inhibitors bind reversibly to the target kinase in an inactive conformation, whereby the DFG motif is directed away from the ATP-binding site (the DFG-out conformation). Type III inhibitors bind remotely from the catalytic ATP-binding site whereby they modulate kinase activity in an allosteric manner [6]. They can be further classified into two subtypes: (i) type IIIA inhibitors which bind to a site in the adenine-binding pocket next to the ATP binding site; and (ii) type IIIB inhibitors which bind elsewhere. Type IV inhibitors or substrate-directed inhibitors are allosteric inhibitors that target regions outside the ATP-binding sites but do not overlap with type III inhibitors [7]. Type V inhibitors are bivalent inhibitors that bind irreversibly to the active kinase sites and peptide motifs representing the substrate targeted by the kinase [8]. Type VI inhibitors bind covalently to their kinase target via the interaction of the reactive electrophilic groups of the inhibitors with primarily the nucleophilic cysteines [9]. Type VII inhibitors are defined as nonclassical allosteric inhibitors that target the extracellular domain of a receptor tyrosine kinase.
Table 1. The characteristics of different type of kinase inhibitors.
Figure 1. FDA-approved small molecule kinase inhibitors for the treatment of cancer and non-cancer conditions.To date, the Food and Drug Administration (FDA) has authorized more than 70 small-molecule KIs in the United States (Figure 1) [10], and many more are under evaluation. In the Malaysia context, there are quite good access and coverage of treatment for some of the drugs. Blood malignancies such as leukaemia and lymphoma have a relatively high coverage of treatments at about 96% and 75%, respectively (Figure 2). However, coverage of other targeted treatments for solid tumours such as lung, breast, kidney, ovarian and colon cancers is poor, ranging from 7 to 24%. It is evident that KIs are in high demand in drug research, particularly for cancer treatment. Imatinib (Gleevec) was the first KI that has gained approval for human therapy, and a game-changer for the subsequent development of kinase-targeted drugs. The introduction of imatinib into clinical practice in 2001 has turned chronic myeloid leukaemia (CML) from a potentially lethal disease into a condition that can be managed and has dramatically improved the patients’ prognosis [11]. Imatinib is the first-generation KI targeting Bcr-Abl fusion kinase that drives CML. However, the emergence of mutations within the BCR-ABL kinase domain has resulted in the development of resistance to imatinib therapy. The second-generation Bcr-Abl KIs including dasatinib, bosutinib and nilotinib were later developed for patients with imatinib resistance and are active against several imatinib-insensitive mutant forms of Bcr-Abl except for T315I mutation [12]. The third-generation Bcr-Abl KI ponatinib is effective against a broad spectrum of mutants including T315I mutation [13].
Figure 2. Coverage of targeted therapies for cancers in Malaysia.
Epidermal growth factor receptor (EGFR) is another oncogenic driver kinase that has been targeted for therapy. Dysregulations in signalling caused by alterations in EGFR and its other closely related members, such as ErbB2 or HER2 have been associated with cancer [14]. Gefitinib and erlotinib are first-generation EGFR KIs approved for treating EGFR mutant non-small cell lung cancer (NSCLC) [15]. Second-generation EGFR KIs like afatinib and dacomitinib are irreversible inhibitors that are more potent than first-generation EGFR KIs against wild-type EGFR and EGFR with Del19 or L858R and display wide activity against numerous ErbB receptors including EGFR, HER2, and HER4 [16,17]. Nevertheless, mutations causing conformational alterations to the receptor and activation of compensatory signalling pathways cause resistance to first- and second-generation inhibitors. Third-generation EGFR KI such as osimertinib is an irreversible inhibitor for cancers with acquired resistance due to secondary T790M mutation [18].
The component of the mitogen-activated protein kinase (MAPK) pathways is another important therapeutic target [19]. Several KIs, notably vemurafenib, dabrafenib, and encorafenib target BRAF, a commonly mutated gene in the MAPK pathway [20]. They exhibit potent inhibitory activity against the BRAF V600E mutant. Additionally, vemurafenib and dabrafenib are also effective against BRAF mutants V600D and V600R [21,22], whereas encorafenib can inhibit V600K mutants and wild-type BRAF [23]. BRAF inhibitors can be coupled with MEK inhibitors such as trametinib, cobimetinib, binimetinib, and selumetinib to provide effective and persistent MAPK pathway inhibition [24]. Other FDA-approved Kis target kinases such as cyclin-dependent kinase (CDK), hepatocyte growth factor (HGF, also known as tyrosine-protein kinase MET), platelet-derived growth factor beta-receptor (PDGFR), fibroblast growth factor receptor (FGFR), Janus kinase (JAK), Bruton’s tyrosine kinase (BTK), mechanistic target of rapamycin (mTOR), colony stimulating factor 1 receptor (CSF1R), Rearranged during Transfection (RET), anaplastic lymphoma kinase (ALK), tropomyosin receptor kinases (TRK) and spleen tyrosine kinase (Syk).
Even though kinase inhibitors represent an innovation in cancer treatment, not every patient can benefit from them. Mutations changing the amino acid sequence, conformation, or expression level of the kinases are widely used by tumour cells as escape mechanisms [25]. This hinders the small molecule drug from accessing the binding site and interfering with protein signalling, resulting in a lack of kinase inhibitor activity and the development of drug resistance. On the other hand, the search for the key molecular player that can be translated into real-world therapy remains challenging. The cancer is characterised by a complex molecular landscape, and is more likely to be caused by alteration of more than one kinase; therefore, elucidating the full disease-kinase relationship is essential. Clearly, research is still required to identify new, potential driver kinases and predictive biomarkers. The current landscape of kinase inhibitors demonstrates the necessity to explore new pathways and new indications in order to achieve their full potential not just for cancer, but also for other diseases.
References
[1] Adam K & Hunter T (2018) Histidine kinases and the missing phosphoproteome from prokaryotes to eukaryotes. Lab Investig 98, 233–247.
[2] Cieśla J, Fraczyk T & Rode W (2011) Phosphorylation of basic amino acid residues in proteins: Important but easily missed. Acta Biochim Pol 58, 137–148.
[3] Blume-Jensen P & Hunter T (2001) Oncogenic kinase signalling. Nature 411, 355–365.
[4] Dar AC & Shokat KM (2011) The evolution of protein kinase inhibitors from antagonists to agonists of cellular signaling. Annu Rev Biochem 80, 769–795
[5] Zuccotto F, Ardini E, Casale E & Angiolini M (2009) Through the “gatekeeper door”: exploiting the active kinase conformation. J Med Chem 53, 2681–2694.
[6] Roskoski R (2016) Classification of small molecule protein kinase inhibitors based upon the structures of their drug-enzyme complexes. Pharmacol Res 103, 26–48.
[7] Gavrin LK & Saiah E (2013) Approaches to discover non-ATP site kinase inhibitors. Med Chem Comm 4, 41–51.
[8] Lamba V & Ghosh I (2012) New directions in targeting protein kinases: focusing upon true allosteric and bivalent inhibitors. Curr Pharm Des 18, 2936–2945.
[9] Martinez R III, Defnet A & Shapiro P (2020) Avoiding or Co-Opting ATP Inhibition: Overview of Type III, IV, V, and VI Kinase Inhibitors. Next Generation Kinase Inhibitors 29–59.
[10] (http://www.brimr.org/PKI/PKIs.htm),
[11] Druker B, Sawyers C, Kantarjian H, Resta D, Reese S, Ford J, Capdeville R & Talpaz M (2001) Activity of a specific inhibitor of the BCR-ABL tyrosine kinase in the blast crisis of chronic myeloid leukemia and acute lymphoblastic leukemia with the Philadelphia chromosome. N Engl J Med 344, 1038–1042.
[12] Hochhaus A, Saussele S, Rosti G, Mahon F-X, Janssen J, Hjorth-Hansen H & Al E (2017) Chronic myeloid leukaemia: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 28(suppl_4, iv41–51.
[13] O’Hare T, Shakespeare W, Zhu X, Eide C, Rivera V, Wang F, Adrian L, Zhou T, Huang W, Xu Q, Metcalf C, Tyner J, Loriaux M, Corbin A, Wardwell S, Ning Y, Keats J, Wang Y, Sundaramoorthi R, Thomas M, Zhou D, Snodgrass J, Commodore L, Sawyer T, Dalgarno D, Deininger M, Druker B & Clackson T (2009) AP24534, a pan-BCR-ABL inhibitor for chronic myeloid leukemia, potently inhibits the T315I mutant and overcomes mutation-based resistance. Cancer Cell 16, 401–412.
[14] Roskoski Jr R (2014) The ErbB/HER family of protein-tyrosine kinases and cancer. Pharmacol Res 79, 34–74.
[15] Riely G, Politi K, Miller V & Pao W (2006) Update on epidermal growth factor receptor mutations in non-small cell lung cancer. Clin Cancer Res 12, 7232–7241.
[16] Hirsh V (2015) Next-generation covalent irreversible kinase inhibitors in NSCLC: focus on afatinib. BioDrugs 29, 167–183.
[17] Ou S & Soo R (2015) Dacomitinib in lung cancer: a “lost generation” EGFR tyrosine-kinase inhibitor from a bygone era? Drug Des Devel Ther 9, 5641–5653.
[18] Finlay M, Anderton M, Ashton S & Al E (2014) Discovery of a potent and selective EGFR inhibitor (AZD9291) of both sensitizing and T790M resistance mutations that spares the wild type form of the receptor. J Med Chem 57, 8249–8267.
[19] Burotto M, Chiou V, Lee J & Kohn E (2014) The MAPK pathway across different malignancies: a new perspective. Cancer 120, 3446–3456.
[20] Savoia P, Fava P, Casoni F & Cremona O (2019) Targeting the ERK signaling pathway in melanoma. Int J Mol Sci 20, 1483
[21] Yang H, Higgins B, Kolinsky K, Packman K, Go Z, Iyer R, Kolis S, Zhao S, Lee R, Grippo J & Al. E (2010) RG7204 (PLX4032), a selective BRAFV600E inhibitor, displays potent antitumor activity in preclinical melanoma models. Cancer Res 70, 5518–5527.
[22] Gentilcore G, Madonna G, Mozzillo N, Ribas A, Cossu A, Palmieri G & Ascierto P (2013) Effect of dabrafenib on melanoma cell lines harbouring the BRAF(V600D/R) mutations. BMC Cancer 13, 17.
[23] Koelblinger P, Thuerigen O & Dummer R (2018) Development of encorafenib for BRAF-mutated advanced melanoma. Curr Opin Oncol 30, 125–133.
[24] Daud A & Tsai K (2017) Management of treatment-related adverse events with agents targeting the MAPK pathway in patients with metastatic melanoma. Oncologist 22, 823–833.
[25] Lovly CM & Shaw AT (2014) Molecular pathways: resistance to kinase inhibitors and implications for therapeutic strategies. Clin Cancer Res 20, 2249-2256.