Tumor Resistance to Molecularly Targeted Agents
James Chen, Peter S. Edelstein, Philip J. Johnson, Robert Lustig, Lucien Ooi
DOI: 10.4236/jct.2011.22033   PDF    HTML     5,477 Downloads   10,135 Views   Citations


Despite the development of new targeted cancer therapies, primary and secondary tumors continue to be a leading cause of suffering and mortality worldwide. The complexity and heterogeneity of malignancies ultimately result in tumor resistance to therapies, such as EGFR inhibitiors, anti-angiogenesis agents, and tyrosine kinase inhibitors. An example of targeted therapies for renal cell carcinoma is presented, including the SAE profile and efficacy of 6 targeted agents. Although survival is improved, resistance and an increased side effect profile diminish the benefits of these agents. New agents are needed which are pathway independent and which can overcome tumor resistance without adding to the side effect profile of current therapies.

Share and Cite:

J. Chen, P. Edelstein, P. Johnson, R. Lustig and L. Ooi, "Tumor Resistance to Molecularly Targeted Agents," Journal of Cancer Therapy, Vol. 2 No. 2, 2011, pp. 258-265. doi: 10.4236/jct.2011.22033.

Conflicts of Interest

The authors declare no conflicts of interest.


[1] E. Finlay and D. Casarett, “Making Difficult Discussions Easier: Using Prognosis to Facilitate Transitions to Hospice,” CA: A Cancer Journal for Clinicians, Vol. 59, No. 4, 2009, pp. 250-263. doi:10.3322/caac.20022
[2] A. Jemal, R. Siegel, E. Ward, Y. Hao, J. Xu and M. J. Thun, “Cancer statistics, 2009,” CA: A Cancer Journal for Clinicians, Vol. 59, No. 4, 2009, pp. 225-249. doi:10.3322/caac.20006
[3] M. J. Horner, L. A. G. Ries, M. Krapcho, N. Neyman, R. Aminou, N. Howlader, S. F. Altekruse, E. J. Feuer, L. Huang, A. Mariotto, B. A. Miller, D. R. Lewis, M. P. Eisner, D. G. Stinchcomb and B. K. Edwards, “SEER Cancer Statistics Review, 1975-2006,” National Cancer Institute, 2009. http://seer.cancer.gov/csr/1975_2006/
[4] S. Begley, “We Fought Cancer...and Cancer Won,” 2008. http://www.newsweek.com/id/157548
[5] F. Grizzi and M. Chiriva-Internati, “Cancer: Looking for Simplicity and Finding Complexity,” Cancer Cell International, Vol. 6, 2006, p. 4. doi:10.1186/1475-2867-6-4
[6] B. T. Hennessy, A. M. Gonzalez-Angulo, M. S. Carey and G. B. Mills, “A Systems Approach to Analysis of Molecular Complexity in Breast Cancer,” Clinical Cancer Research, Vol. 15, No. 2, 2009, pp. 417-419. doi:10.1158/1078-0432.CCR-08-2620
[7] G. Kolata, “As Other Death Rates Fall, Cancer’s Scarcely Moves,” New York Times, 24 April 2009, p. A17.
[8] A. E. Teschendorff, M. Journee, P. A. Absil, R. Sepulchre and C. Caldas, “Elucidating the Altered Transcriptional Programs in Breast Cancer Using Independent Component Analysis,” PLoS Computational Biology, Vol. 3, No. 8, 2007, p. e161. doi:10.1371/journal.pcbi.0030161
[9] M. Bredel, D. M. Scholtens, G. R. Harsh, C. Bredel, J. P. Chandler, J. J. Renfrow, A. K. Yadav, H. Vogel, A. C. Scheck, R. Tibshirani and B. I. Sikic, “A Network Model of a Cooperative Genetic Landscape in Brain Tumors,” The Journal of the American Medical Association, Vol. 302, No. 3, 2009, pp. 261-275. doi:10.1001/jama.2009.997
[10] G. Tonon, “From Oncogene to Network Addiction: The New Frontier of Cancer Genomics and Therapeutics,” Future Oncology, Vol. 4, No. 4, 2008, pp. 569-577. doi:10.2217/14796694.4.4.569
[11] L. B. Saltz, “Progress in Cancer Care: The Hope, the Hype, and the Gap between Reality and Perception,” Journal of Clinical Oncology, Vol. 26, No. 31, 2008, pp. 5020-5021. doi:10.1200/JCO.2008.17.6198
[12] D. J. Stewart and R. Kurzrock, “Cancer: The Road to Amiens,” Journal of Clinical Oncology, Vol. 27, No. 3, 2009, pp. 328-333. doi:10.1200/JCO.2008.18.9621
[13] Q. Cui, Y. Ma, M. Jaramillo, H. Bari, A. Awan, S. Yang, S. Zhang, L. Liu, M. Lu, M. O’Connor-McCourt, E. O. Purisima and E. Wang, “A Map of Human Cancer Signaling,” Molecular Systems Biology, Vol. 3, 2007, p. 152. doi:10.1038/msb4100200
[14] Y. J. Huang, D. Hang, L. J. Lu, L. Tong, M. B. Gerstein and G. T. Montelione, “Targeting the Human Cancer Path- Way Protein Interaction Network by Structural Genomics,” Molecular and Cellular Proteomics, Vol. 7, No. 10, 2008, pp. 2048-2060. doi:10.1074/mcp.M700550-MCP200
[15] E. A. Golemis, I. G. Serebriiskii, N. Skobeleva, E. N. Pugacheva, M. K. Singh, N. Tikhmyanova, E. Izum- chenko, S. Bluestein, W. Gao and W. Yun, “The Role of Signaling Hubs in Metastasis,” 2006. www.fccc.edu/docs/sci_report/Golemis.pdf
[16] E. A. Hopper-Borge, R. E. Nasto, V. Ratushny, L. M. Weiner, E. A. Golemis and I. Astsaturov, “Mechanisms of Tumor Resistance to EGFR-Targeted Therapies,” Expert Opinion on Therapeutic Targets, Vol. 13, No. 3, 2009, pp. 339-362. doi:10.1517/14712590902735795
[17] G. Bergers and D. Hanahan, “Modes of Resistance to Anti-Angiogenic Therapy,” Nature Reviews Cancer, Vol. 8, No. 8, 2008, pp. 592-603. doi:10.1038/nrc2442
[18] A. K. Lucio-Eterovic, Y. Piao and J. F. de Groot, “Mediators of Glioblastoma Resistance and Invasion during Antivascular Endothelial Growth Factor Therapy,” Clinical Cancer Research, Vol. 15, No. 14, 2009, pp. 4589-4599. doi:10.1158/1078-0432.CCR-09-0575
[19] J. M. Ebos, C. R. Lee and R. S. Kerbel, “Tumor and Host-Mediated Pathways of Resistance and Disease Progression in Response to Antiangiogenic Therapy,” Clinical Cancer Research, Vol. 15, No. 16, 2009, pp. 5020-5025. doi:10.1158/1078-0432.CCR-09-0095
[20] J. A. Engelman and P. A. Janne, “Mechanisms of Acquired Resistance to Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors in Non-Small Cell Lung Cancer,” Clinical Cancer Research, Vol. 14, No. 10, 2008, pp. 2895-2899. doi:10.1158/1078-0432.CCR-07-2248
[21] M. Guix, A. C. Faber, S. E. Wang, M. G. Olivares, Y. Song, S. Qu, C. Rinehart, B. Seidel, D. Yee, C. L. Arteaga and J. A. Engelman, “Acquired Resistance to EGFR Tyrosine Kinase Inhibitors in Cancer Cells is Mediated by Loss of IGF-Binding Proteins,” The Journal Clinical Investigation, Vol. 118, No. 7, 2008, pp. 2609- 2619.
[22] H. E. Jones, J. M. Gee, I. R. Hutcheson, J. M. Knowlden, D. Barrow and R. I. Nicholson, “Growth Factor Receptor Interplay and Resistance in Cancer,” Endocrine-Related Cancer, Vol. 13, 2006, pp. S45-51. doi:10.1677/erc.1.01275
[23] A. Maleddu, M. A. Pantaleo, M. Nannini, M. di Battista, M. Saponara, C. Lolli and G. Biasco, “Mechanisms of Secondary Resistance to Tyrosine Kinase Inhibitors in Gastrointestinal Stromal Tumours (Review),” Oncology Reports, Vol. 21, No. 6, 2009, pp. 1359-1366. doi:10.3892/or_00000361
[24] J. Zhang, P. L. Yang and N. S. Gray, “Targeting Cancer with Small Molecule Kinase Inhibitors,” Nature Reviews Cancer, Vol. 9, No. 1, 2009, pp. 28-39. doi:10.1038/nrc2559
[25] A. P. Crijns, R. S. Fehrmann, S. de Jong, F. Gerbens, G. J. Meersma, H. G. Klip, H. Hollema, R. M. Hofstra, G. J. te Meerman, E. G. de Vries and A. G. van der Zee, “Survival-Related Profile, Pathways, and Transcription Factors in Ovarian Cancer,” PLoS Medicine, Vol. 6, No. 2, 2009, p. e24. doi:10.1371/journal.pmed.1000024
[26] S. Klein and A. Levitzki, “Signal Transduction Therapy for Cancer—Whither Now?” Current Signal Transduction Therapy, Vol. 1, No. 1, 2006, pp. 1-12. doi:10.2174/157436206775269244
[27] B. I. Rini, S. C. Campbell and B. Escudier, “Renal Cell Carcinoma,” The Lancet, Vol. 373, No. 9669, 2009, pp. 1119-1132. doi:10.1016/S0140-6736(09)60229-4
[28] M. B. Atkins, “Molecularly Targeted Therapy for Advanced Renal Cell Carcinoma,” 2009. http://www.utdol.com/home/content/topic.do?topicKey=gucancer/14941&view=print
[29] T. K. Choueiri, “Metastatic Renal Cell Carcinoma: A Guide to Therapy Based on Current Evidence,” Urology Annals, Vol. 1, No. 1, 2009, pp. 9-14. doi:10.4103/0974-7796.48781
[30] Canadian Kidney Cancer Forum 2009, “Management of Kidney Cancer: Canadian Kidney Cancer Forum Consensus Update,” Canadian Urological Association Journal, Vol. 3, No. 3, 2009, pp. 200-204.
[31] J. Bellmunt and M. Guix, “The Medical Management of Metastatic Renal Cell Carcinoma: Integrating New Guidelines and Recommendations,” British Journal of Urology International, Vol. 103, No. 5, 2009, pp. 572-577. doi:10.1111/j.1464-410X.2008.08336.x
[32] C. Porta and C. Szczylik, “Tolerability of First-Line Therapy for Metastatic Renal Cell Carcinoma,” Cancer Treat Reviews, Vol. 35, No. 3, 2009, pp. 297-307. doi:10.1016/j.ctrv.2008.12.003
[33] M. Basso, A. Cassano and C. Barone, “A Survey of Therapy for Advanced Renal Cell Carcinoma,” Urologic Oncology, Vol. 28, No. 2, 2009, pp. 121-133. doi:10.1016/j.urolonc.2009.04.015
[34] National Cancer Institute, “FDA Approval for Everolimus,” 2009. http://www.cancer.gov/cancertopics/druginfo/fda-everolimus
[35] GlaxoSmithKline, “FDA Approves GlaxoSmithKline’s Votrient? for Advanced Renal Cell Cancer,” 2009. http://www.gsk.com/media/pressreleases/2009/2009_pressrelease_10113.htm
[36] P. H. Patel, P. L. Senico, R. E. Curiel and R. J. Motzer, “Phase I Study Combining Treatment with Temsirolimus and Sunitinib Malate in Patients with Advanced Renal Cell Carcinoma,” Clinical Genitourinary Cancer, Vol. 7, No. 1, 2009, pp. 24-27. doi:10.3816/CGC.2009.n.004
[37] G. Di Lorenzo, R. Autorino and C. N. Sternberg, “Metastatic Renal Cell Carcinoma: Recent Advances in the Targeted Therapy Era,” European Urology, Vol. 56, No. 6, 2009, pp. 891-1104.
[38] J. B. Easton, R. T. Kurmasheva and P. J. Houghton, “IRS-1: Auditing the Effectiveness of mTOR Inhibitors,” Cancer Cell, Vol. 9, No. 3, 2006, pp. 153-155. doi:10.1016/j.ccr.2006.02.027
[39] M. B. Atkins, M. S. Ernstoff, R. A. Figlin, K. T. Flaherty, D. J. George, W. G. Kaelin Jr., E. D. Kwon, T. A. Libermann, W. M. Linehan, D. F. McDermott, A. C. Ochoa, A. J. Pantuck, B. I. Rini, M. A. Rosen, J. A. Sosman, V. P. Sukhatme, J. W. Vieweg, C. G. Wood and L. King, “Innovations and Challenges in Renal Cell Carcinoma: Summary Statement from the Second Cambridge Conference,” Clinical Cancer Research, Vol. 13, No. 2, 2007, pp. 667s-670s.
[40] J. Brugarolas, “Molecular Pathways and Targeted Thera- pies for Renal Cell Carcinom,” ASCO 2009, Educational Book 2009, pp. 710-715.
[41] GenomeNet, “Kyoto Encyclopedia of Genes and Genomes (KEGG),” http://www.genome.jp/kegg/kegg1.html
[42] R. T. Kurmasheva, S. Huang and P. J. Houghton, “Predicted mechanisms of resistance to mTOR inhibitors,” British Journal of Cancer, Vol. 95, No. 8, 2006, pp. 955-960. doi:10.1038/sj.bjc.6603353
[43] K. E. O’Reilly, F. Rojo, Q. B. She, D. Solit, G. B. Mills, D. Smith, H. Lane, F. Hofmann, D. J. Hicklin, D. L. Ludwig, J. Baselga and N. Rosen, “mTOR Inhibition Induces Upstream Receptor Tyrosine Kinase Signaling and Activates Akt,” Cancer Research, Vol. 66, No. 3, 2006, pp. 1500-1508. doi:10.1158/0008-5472.CAN-05-2925
[44] M. A. Arap, A. G. Kann, G. S. Fernandes, A. C. Buzaid, S. Arap and F. C. Maluf, “New Directions in the Management of Renal Cell Carcinoma,” Cancer Therapy, Vol. 6, 2008, pp. 11-24.
[45] E. J. Abel and C. G. Wood, “Cytoreductive Nephrectomy for Metastatic RCC in the Era of Targeted Therapy,” Nature Reviews Urology, Vol. 6, No. 7, 2009, pp. 375-383. doi:10.1038/nrurol.2009.102
[46] R. A. Figlin, “Sequencing of Drugs in the Treatment of Kidney Cancer,” 2009. http://cme.medscape.com/viewarticle/702103_print
[47] B. I. Rini, “ASCO 2009: Latest Updates on Renal Carcinoma,” 2009. http://cme.medscape.com/viewarticle/706713_print
[48] B. I. Rini, G. Wilding, G. Hudes, W. M. Stadler, S. Kim, J. Tarazi, B. Rosbrook, P. C. Trask, L. Wood and J. P. Dutcher, “Phase II Study of Axitinib in Sorafenib- Refractory Metastatic Renal Cell Carcinoma,” Journal of Clinical Oncology, Vol. 27, No. 27, 2009, pp. 4462-4468. doi:10.1200/JCO.2008.21.7034
[49] W. M. Stadler, “Effective Therapy for Metastatic Renal Cancer, Whither to Now,” Journal of Clinical Oncology, Vol. 27, No. 22, 2009, pp. 3573-3574. doi:10.1200/JCO.2009.22.5250
[50] Y. Je, F. A. Schutz and T. K. Choueiri, “Risk of Bleeding with Vascular Endothelial Growth Factor Receptor Tyro- sine-Kinase Inhibitors Sunitinib and Sorafenib: A Systematic Review and Meta-Analysis of Clinical Trials,” The Lancet Oncology, Vol. 10, No. 10, 2009, pp. 967-974. doi:10.1016/S1470-2045(09)70222-0
[51] S. R. Nalluri, D. Chu, R. Keresztes, X. Zhu and S. Wu, “Risk of Venous Thromboembolism with the Angiogenesis Inhibitor Bevacizumab in Cancer Patients: A Meta-Analysis,” The Journal of the American Medical Association, Vol. 300, No. 19, 2008, pp. 2277-2285. doi:10.1001/jama.2008.656

Copyright © 2024 by authors and Scientific Research Publishing Inc.

Creative Commons License

This work and the related PDF file are licensed under a Creative Commons Attribution 4.0 International License.