Top

Published in:

01-07-2014 | Review Article

The mechanism of chemoresistance against tyrosine kinase inhibitors in malignant glioma

Authors: Mitsutoshi Nakada, Daisuke Kita, Takuya Watanabe, Yutaka Hayashi, Jun-ichiro Hamada

Published in: Brain Tumor Pathology | Issue 3/2014

Abstract

Glioblastoma (GBM) is one of the most lethal malignancies in humans, and novel therapeutic strategies are urgently required for its treatment. Tyrosine kinases (TKs) play a pivotal role in intercellular signal transduction and regulate crucial processes of tumor cell biological activities in GBM. This information provides the basis for the molecular target therapies for GBMs. TK inhibitors (TKIs) are expected to be effective therapeutic strategies. However, one important limitation is that GBMs exhibit marked resistance to the TKIs currently available, yet the mechanisms underlying TKI resistance have not been fully characterized. In the current review, we will address the varieties of chemoresistance mechanisms against TKIs in GBM. The mechanisms responsible for TKI refractoriness in GBMs are divided into 2 aspects. The first includes tumor-related concerns, such as a lack of target expression, the multiplicity of targets, redundancy, the appearance of resistant cells, and tumor changes in characteristics. The second includes drug-related concerns, such as inefficient drug effects, delivery, pharmacokinetics, and intolerable side effects. A better understanding of these mechanisms is needed to develop accurate tests to predict the lack of response to TKIs and for developing novel approaches aimed at overcoming the resistance to TKIs.

Dumur CI, Idowu MO, Powers CN (2013) Targeting tyrosine kinases in cancer: the converging roles of cytopathology and molecular pathology in the era of genomic medicine. Cancer Cytopathol 121:61–71PubMedCrossRef

Nakada M, Kita D, Watanabe T, Hayashi Y, Teng L, Pyko IV, Hamada J (2011) Aberrant signaling pathways in glioma. Cancers 3:3242–3278PubMedCentralPubMedCrossRef

Hegi ME, Rajakannu P, Weller M (2012) Epidermal growth factor receptor: a re-emerging target in glioblastoma. Curr Opin Neurol 25:774–779PubMedCrossRef

Tanaka S, Louis DN, Curry WT, Batchelor TT, Dietrich J (2013) Diagnostic and therapeutic avenues for glioblastoma: no longer a dead end? Nat Rev Clin Oncol 10:14–26PubMedCrossRef

Chi AS, Batchelor TT, Kwak EL, Clark JW, Wang DL, Wilner KD, Louis DN, Iafrate AJ (2012) Rapid radiographic and clinical improvement after treatment of a MET-amplified recurrent glioblastoma with a mesenchymal-epithelial transition inhibitor. J Clin Oncol 30:e30–e33PubMedCrossRef

Prados MD, Chang SM, Butowski N, DeBoer R, Parvataneni R, Carliner H, Kabuubi P, Ayers-Ringler J, Rabbitt J, Page M, Fedoroff A, Sneed PK, Berger MS, McDermott MW, Parsa AT, Vandenberg S, James CD, Lamborn KR, Stokoe D, Haas-Kogan DA (2009) Phase II study of erlotinib plus temozolomide during and after radiation therapy in patients with newly diagnosed glioblastoma multiforme or gliosarcoma. J Clin Oncol 27:579–584PubMedCentralPubMedCrossRef

Raizer JJ, Abrey LE, Lassman AB, Chang SM, Lamborn KR, Kuhn JG, Yung WK, Gilbert MR, Aldape KA, Wen PY, Fine HA, Mehta M, Deangelis LM, Lieberman F, Cloughesy TF, Robins HI, Dancey J, Prados MD (2010) A phase II trial of erlotinib in patients with recurrent malignant gliomas and nonprogressive glioblastoma multiforme postradiation therapy. Neuro Oncol 12:95–103PubMedCentralPubMedCrossRef

Peereboom DM, Shepard DR, Ahluwalia MS, Brewer CJ, Agarwal N, Stevens GH, Suh JH, Toms SA, Vogelbaum MA, Weil RJ, Elson P, Barnett GH (2010) Phase II trial of erlotinib with temozolomide and radiation in patients with newly diagnosed glioblastoma multiforme. J Neurooncol 98:93–99PubMedCrossRef

Mukasa A, Wykosky J, Ligon KL, Chin L, Cavenee WK, Furnari F (2010) Mutant EGFR is required for maintenance of glioma growth in vivo, and its ablation leads to escape from receptor dependence. Proc Natl Acad Sci USA 107:2616–2621PubMedCentralPubMedCrossRef

10.

Weller M, Stupp R, Hegi M, Wick W (2012) Individualized targeted therapy for glioblastoma: fact or fiction? Cancer J 18:40–44PubMedCrossRef

11.

Szerlip NJ, Pedraza A, Chakravarty D, Azim M, McGuire J, Fang Y, Ozawa T, Holland EC, Huse JT, Jhanwar S, Leversha MA, Mikkelsen T, Brennan CW (2012) Intratumoral heterogeneity of receptor tyrosine kinases EGFR and PDGFRA amplification in glioblastoma defines subpopulations with distinct growth factor response. Proc Natl Acad Sci USA 109:3041–3046PubMedCentralPubMedCrossRef

12.

Stommel JM, Kimmelman AC, Ying H, Nabioullin R, Ponugoti AH, Wiedemeyer R, Stegh AH, Bradner JE, Ligon KL, Brennan C, Chin L, DePinho RA (2007) Coactivation of receptor tyrosine kinases affects the response of tumor cells to targeted therapies. Science 318:287–290PubMedCrossRef

13.

Network CGAR (2008) Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature 455:1061–1068CrossRef

14.

Parsons DW, Jones S, Zhang X, Lin JC, Leary RJ, Angenendt P, Mankoo P, Carter H, Siu IM, Gallia GL, Olivi A, McLendon R, Rasheed BA, Keir S, Nikolskaya T, Nikolsky Y, Busam DA, Tekleab H, Diaz LA Jr, Hartigan J, Smith DR, Strausberg RL, Marie SK, Shinjo SM, Yan H, Riggins GJ, Bigner DD, Karchin R, Papadopoulos N, Parmigiani G, Vogelstein B, Velculescu VE, Kinzler KW (2008) An integrated genomic analysis of human glioblastoma multiforme. Science 321:1807–1812PubMedCentralPubMedCrossRef

15.

Rich JN, Rasheed BK, Yan H (2004) EGFR mutations and sensitivity to gefitinib. N Engl J Med 351:1260–1261PubMedCrossRef

16.

Mellinghoff IK, Wang MY, Vivanco I, Haas-Kogan DA, Zhu S, Dia EQ, Lu KV, Yoshimoto K, Huang JH, Chute DJ, Riggs BL, Horvath S, Liau LM, Cavenee WK, Rao PN, Beroukhim R, Peck TC, Lee JC, Sellers WR, Stokoe D, Prados M, Cloughesy TF, Sawyers CL, Mischel PS (2005) Molecular determinants of the response of glioblastomas to EGFR kinase inhibitors. N Engl J Med 353:2012–2024PubMedCrossRef

17.

De Witt Hamer PC (2010) Small molecule kinase inhibitors in glioblastoma: a systematic review of clinical studies. Neuro Oncol 12:304–316PubMedCentralPubMedCrossRef

18.

Snuderl M, Fazlollahi L, Le LP, Nitta M, Zhelyazkova BH, Davidson CJ, Akhavanfard S, Cahill DP, Aldape KD, Betensky RA, Louis DN, Iafrate AJ (2011) Mosaic amplification of multiple receptor tyrosine kinase genes in glioblastoma. Cancer Cell 20:810–817PubMedCrossRef

19.

Little SE, Popov S, Jury A, Bax DA, Doey L, Al-Sarraj S, Jurgensmeier JM, Jones C (2012) Receptor tyrosine kinase genes amplified in glioblastoma exhibit a mutual exclusivity in variable proportions reflective of individual tumor heterogeneity. Cancer Res 72:1614–1620PubMedCrossRef

20.

Reardon DA, Desjardins A, Vredenburgh JJ, Gururangan S, Friedman AH, Herndon JE 2nd, Marcello J, Norfleet JA, McLendon RE, Sampson JH, Friedman HS (2010) Phase 2 trial of erlotinib plus sirolimus in adults with recurrent glioblastoma. J Neurooncol 96:219–230PubMedCentralPubMedCrossRef

21.

Bao S, Wu Q, McLendon RE, Hao Y, Shi Q, Hjelmeland AB, Dewhirst MW, Bigner DD, Rich JN (2006) Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. Nature 444:756–760PubMedCrossRef

22.

Huang Z, Cheng L, Guryanova OA, Wu Q, Bao S (2010) Cancer stem cells in glioblastoma–molecular signaling and therapeutic targeting. Protein Cell 1:638–655PubMedCrossRef

23.

Ozvegy-Laczka C, Cserepes J, Elkind NB, Sarkadi B (2005) Tyrosine kinase inhibitor resistance in cancer: role of ABC multidrug transporters. Drug Resist Update 8:15–26CrossRef

24.

Patrawala L, Calhoun T, Schneider-Broussard R, Zhou J, Claypool K, Tang DG (2005) Side population is enriched in tumorigenic, stem-like cancer cells, whereas ABCG2+ and ABCG2− cancer cells are similarly tumorigenic. Cancer Res 65:6207–6219PubMedCrossRef

25.

Bleau AM, Hambardzumyan D, Ozawa T, Fomchenko EI, Huse JT, Brennan CW, Holland EC (2009) PTEN/PI3K/Akt pathway regulates the side population phenotype and ABCG2 activity in glioma tumor stem-like cells. Cell Stem Cell 4:226–235PubMedCentralPubMedCrossRef

26.

Ozvegy-Laczka C, Hegedus T, Varady G, Ujhelly O, Schuetz JD, Varadi A, Keri G, Orfi L, Nemet K, Sarkadi B (2004) High-affinity interaction of tyrosine kinase inhibitors with the ABCG2 multidrug transporter. Mol Pharmacol 65:1485–1495PubMedCrossRef

27.

Yanase K, Tsukahara S, Asada S, Ishikawa E, Imai Y, Sugimoto Y (2004) Gefitinib reverses breast cancer resistance protein-mediated drug resistance. Mol Cancer Ther 3:1119–1125PubMed

28.

Wang XK, Fu LW (2010) Interaction of tyrosine kinase inhibitors with the MDR-related ABC transporter proteins. Curr Drug Metab 11:618–628PubMedCrossRef

29.

Nakada M, Nakada S, Demuth T, Tran NL, Hoelzinger DB, Berens ME (2007) Molecular targets of glioma invasion. Cell Mol Life Sci 64:458–478PubMedCrossRef

30.

Nakada M, Kita D, Teng L, Pyko IV, Watanabe T, Hayashi Y, Hamada J (2013) Receptor tyrosine kinases: principles and functions in glioma invasion. Adv Exp Med Biol 986:143–170PubMedCrossRef

31.

Hatzikirou H, Basanta D, Simon M, Schaller K, Deutsch A (2012) ‘Go or grow’: the key to the emergence of invasion in tumour progression? Math Med Biol 29:49–65PubMedCrossRef

32.

Keunen O, Johansson M, Oudin A, Sanzey M, Rahim SA, Fack F, Thorsen F, Taxt T, Bartos M, Jirik R, Miletic H, Wang J, Stieber D, Stuhr L, Moen I, Rygh CB, Bjerkvig R, Niclou SP (2011) Anti-VEGF treatment reduces blood supply and increases tumor cell invasion in glioblastoma. Proc Natl Acad Sci USA 108:3749–3754PubMedCentralPubMedCrossRef

33.

Kreisl TN, Kim L, Moore K, Duic P, Royce C, Stroud I, Garren N, Mackey M, Butman JA, Camphausen K, Park J, Albert PS, Fine HA (2009) Phase II trial of single-agent bevacizumab followed by bevacizumab plus irinotecan at tumor progression in recurrent glioblastoma. J Clin Oncol 27:740–745PubMedCentralPubMedCrossRef

34.

Friedman HS, Prados MD, Wen PY, Mikkelsen T, Schiff D, Abrey LE, Yung WK, Paleologos N, Nicholas MK, Jensen R, Vredenburgh J, Huang J, Zheng M, Cloughesy T (2009) Bevacizumab alone and in combination with irinotecan in recurrent glioblastoma. J Clin Oncol 27:4733–4740PubMedCrossRef

35.

Paez-Ribes M, Allen E, Hudock J, Takeda T, Okuyama H, Vinals F, Inoue M, Bergers G, Hanahan D, Casanovas O (2009) Antiangiogenic therapy elicits malignant progression of tumors to increased local invasion and distant metastasis. Cancer Cell 15:220–231PubMedCentralPubMedCrossRef

36.

Ebos JM, Lee CR, Cruz-Munoz W, Bjarnason GA, Christensen JG, Kerbel RS (2009) Accelerated metastasis after short-term treatment with a potent inhibitor of tumor angiogenesis. Cancer Cell 15:232–239PubMedCrossRef

37.

Batchelor TT, Sorensen AG, di Tomaso E, Zhang WT, Duda DG, Cohen KS, Kozak KR, Cahill DP, Chen PJ, Zhu M, Ancukiewicz M, Mrugala MM, Plotkin S, Drappatz J, Louis DN, Ivy P, Scadden DT, Benner T, Loeffler JS, Wen PY, Jain RK (2007) AZD2171, a pan-VEGF receptor tyrosine kinase inhibitor, normalizes tumor vasculature and alleviates edema in glioblastoma patients. Cancer Cell 11:83–95PubMedCentralPubMedCrossRef

38.

Vivanco I, Robins HI, Rohle D, Campos C, Grommes C, Nghiemphu PL, Kubek S, Oldrini B, Chheda MG, Yannuzzi N, Tao H, Zhu S, Iwanami A, Kuga D, Dang J, Pedraza A, Brennan CW, Heguy A, Liau LM, Lieberman F, Yung WK, Gilbert MR, Reardon DA, Drappatz J, Wen PY, Lamborn KR, Chang SM, Prados MD, Fine HA, Horvath S, Wu N, Lassman AB, DeAngelis LM, Yong WH, Kuhn JG, Mischel PS, Mehta MP, Cloughesy TF, Mellinghoff IK (2012) Differential sensitivity of glioma- versus lung cancer-specific EGFR mutations to EGFR kinase inhibitors. Cancer Discov 2:458–471PubMedCentralPubMedCrossRef

39.

Schwechheimer K, Huang S, Cavenee WK (1995) EGFR gene amplification—rearrangement in human glioblastomas. Int J Cancer 62:145–148PubMedCrossRef

40.

Leis JF, Stepan DE, Curtin PT, Ford JM, Peng B, Schubach S, Druker BJ, Maziarz RT (2004) Central nervous system failure in patients with chronic myelogenous leukemia lymphoid blast crisis and Philadelphia chromosome positive acute lymphoblastic leukemia treated with imatinib (STI-571). Leuk Lymphoma 45:695–698PubMedCrossRef

41.

Glavinas H, Krajcsi P, Cserepes J, Sarkadi B (2004) The role of ABC transporters in drug resistance, metabolism and toxicity. Curr Drug Deliv 1:27–42PubMedCrossRef

42.

Dai H, Marbach P, Lemaire M, Hayes M, Elmquist WF (2003) Distribution of STI-571 to the brain is limited by P-glycoprotein-mediated efflux. J Pharmacol Exp Ther 304:1085–1092PubMedCrossRef

43.

Burger H, van Tol H, Boersma AW, Brok M, Wiemer EA, Stoter G, Nooter K (2004) Imatinib mesylate (STI571) is a substrate for the breast cancer resistance protein (BCRP)/ABCG2 drug pump. Blood 104:2940–2942PubMedCrossRef

44.

Polli JW, Olson KL, Chism JP, John-Williams LS, Yeager RL, Woodard SM, Otto V, Castellino S, Demby VE (2009) An unexpected synergist role of P-glycoprotein and breast cancer resistance protein on the central nervous system penetration of the tyrosine kinase inhibitor lapatinib (N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[5-({[2-(methylsulfonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine; GW572016). Drug Metab Dispos 37:439–442PubMedCrossRef

45.

Agarwal S, Manchanda P, Vogelbaum MA, Ohlfest JR, Elmquist WF (2013) Function of the blood–brain barrier and restriction of drug delivery to invasive glioma cells: findings in an orthotopic rat xenograft model of glioma. Drug Metab Dispos 41:33–39PubMedCentralPubMedCrossRef

46.

Kodaira H, Kusuhara H, Ushiki J, Fuse E, Sugiyama Y (2010) Kinetic analysis of the cooperation of P-glycoprotein (P-gp/Abcb1) and breast cancer resistance protein (Bcrp/Abcg2) in limiting the brain and testis penetration of erlotinib, flavopiridol, and mitoxantrone. J Pharmacol Exp Ther 333:788–796PubMedCrossRef

47.

Elmeliegy MA, Carcaboso AM, Tagen M, Bai F, Stewart CF (2011) Role of ATP-binding cassette and solute carrier transporters in erlotinib CNS penetration and intracellular accumulation. Clin Cancer Res 17:89–99PubMedCentralPubMedCrossRef

48.

Tang SC, Lankheet NA, Poller B, Wagenaar E, Beijnen JH, Schinkel AH (2012) P-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2) restrict brain accumulation of the active sunitinib metabolite N-desethyl sunitinib. J Pharmacol Exp Ther 341:164–173PubMedCrossRef

49.

van Erp NP, Gelderblom H, Guchelaar HJ (2009) Clinical pharmacokinetics of tyrosine kinase inhibitors. Cancer Treat Rev 35:692–706PubMedCrossRef

50.

Del Vecchio CA, Li G, Wong AJ (2012) Targeting EGF receptor variant III: tumor-specific peptide vaccination for malignant gliomas. Expert Rev Vaccines 11:133–144PubMedCrossRef

Title: The mechanism of chemoresistance against tyrosine kinase inhibitors in malignant glioma
Authors: Mitsutoshi Nakada
Daisuke Kita
Takuya Watanabe
Yutaka Hayashi
Jun-ichiro Hamada
Publication date: 01-07-2014
Publisher: Springer Japan
Published in: Brain Tumor Pathology / Issue 3/2014
Print ISSN: 1433-7398
Electronic ISSN: 1861-387X
DOI: https://doi.org/10.1007/s10014-013-0174-9

Keynote webinar | Spotlight on medication adherence

Springer Medicine

The mechanism of chemoresistance against tyrosine kinase inhibitors in malignant glioma

Abstract

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 3/2014

Primary CNS lymphoma arising in the region of the optic nerve presenting as loss of vision: 2 case reports, including a patient with a massive intracerebral hemorrhage

Pitfalls of conservative treatments of multiple probable cerebral cavernous malformations (CCMs): clinicopathological features of CCMs coexisting with vasculogenic mimicry in an anaplastic oligodendroglioma

A case report of sarcoma of the sella caused by postoperative radiotherapy for a prolactin-producing pituitary adenoma

Preface to special edition

Comparison of magnetic resonance imaging with invasive histological findings of Langerhans cell histiocytosis

Epithelioid glioblastoma arising from pleomorphic xanthoastrocytoma with the BRAF V600E mutation