Circumventing Resistance to Kinase-Inhibitor Therapy
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《新英格兰医药杂志》
Throughout its history, chronic myeloid leukemia (CML) has set precedents for cancer research and therapy, ranging from the identification of the first specific chromosomal abnormality associated with cancer to the development of imatinib as a specific, targeted therapy for the disease.1 In this issue of the Journal, two articles2,3 continue this tradition by describing how an understanding of resistance to imatinib has led to a strategy for circumventing resistance. These articles — one concerning nilotinib and the other dasatinib — are of fundamental importance for at least three reasons. First, they provide immediate hope for patients in whom CML cells have developed resistance to imatinib. Second, they demonstrate the clinical value of understanding the molecular basis of drug resistance. Third, they show that the pace of new drug development can be impressively rapid.
The success of imatinib as a treatment for CML can be attributed to the critical role of the BCR-ABL tyrosine kinase in causing the disease and the specificity of imatinib as an ABL kinase inhibitor.1 The clinical activity of imatinib is highest in patients with chronic-phase CML.4,5 Although the response rate in patients with accelerated-phase or blast-phase disease is quite high, most such patients have a relapse. Ninety-five percent of patients are in chronic phase at diagnosis; in these patients who are treated with imatinib, blood counts will return to normal in 98 percent, and in 86 percent the Philadelphia chromosome will disappear — in other words, they will have a complete cytogenetic response. With a median follow-up of 54 months, the overall relapse rate for patients with newly diagnosed chronic-phase CML who were treated with imatinib was 16 percent, but for patients with a complete cytogenetic response, the relapse rate was 7 percent.6 Among patients in whom BCR-ABL messenager RNA (mRNA) levels were reduced by at least 3 log, the relapse rate at 54 months was only 3 percent, and none of these patients had progression to the accelerated phase or blast crisis.
If imatinib is performing so well, why are new drugs needed? One reason is that patients in relapse urgently need new therapies. Furthermore, it is not clear that the apparent trend of decreasing relapse rates over time will persist, and even if it does, the absolute number of patients who have a relapse will increase over time. And even though most patients who are treated with imatinib achieve a 3-log reduction in leukemic-cell burden, BCR-ABL transcripts are undetectable in only a few; in most of these patients, moreover, the disease recurs if imatinib is discontinued. Thus, even patients with well-controlled disease have a reservoir of leukemic cells from which relapse may occur.
Studies of patients in relapse have shown that mutations in the kinase domain of BCR-ABL are the predominant mechanism underlying acquired drug resistance to imatinib; another mechanism in some patients is amplification of the BCR-ABL fusion gene.7 Mutations have been observed to affect at least 25 amino acids scattered throughout the ABL kinase domain, and each of them reduces the sensitivity of the kinase to imatinib.
Structural biology has made major contributions to the understanding of imatinib resistance and the design of new inhibitors. The crystal structure of ABL in a complex with imatinib shows that imatinib binds to a unique, inactive conformation of the ABL kinase domain in which the activation loop is in a closed position.8 Mutations that confer resistance to imatinib affect residues that are directly involved in drug binding, that impair the ability of the kinase domain to undergo the extensive conformational changes required for imatinib binding, or that favor the active conformation of the kinase to which imatinib is unable to bind.
Information from the crystal structure suggested two approaches for the circumventing of resistance. One avenue was the modification of imatinib in such a way that the drug binds more tightly to the ABL kinase. This modification was accomplished by chemists at Novartis in the design of nilotinib.9 A second approach was the development of a compound with an entirely different chemical scaffold. This tack, taken by scientists at Bristol-Myers Squibb, was based on the finding that SRC inhibitors also inhibit the wild-type ABL kinase and most imatinib-resistant mutations.10 (SRC is a protein tyrosine kinase that acts as a signal transducer in several molecular pathways within the cell.) Thus, dasatinib, originally synthesized as a SRC-family inhibitor, was tested for its ability to inhibit ABL and imatinib-resistant mutations.11 Both nilotinib and dasatinib are more potent ABL inhibitors than is imatinib and inhibit all tested imatinib-resistant mutations except T315I.
Consistent with the preclinical profiles of nilotinib and dasatinib, responses in the phase 1 trials of these drugs were seen in patients with all imatinib-resistant mutations except T315I.2,3 Responses were also seen in patients with resistance that was not caused by mutations, a finding that may relate to the high potency of these drugs. Both drugs have unique side effects, including pleural effusions with dasatinib and elevated liver enzyme levels and a prolongation of corrected QT intervals with nilotinib. The question as to whether additional side effects will be observed over time will require larger studies and longer follow-up. Response rates in patients with chronic-phase CML were impressive and have thus far been durable, but responses in accelerated-phase and blast-phase disease were lower, and relapses have been common. For this reason, other strategies are required for the advanced phases of CML and for patients with the T315I ABL mutation.
Nilotinib and dasatinib have immediate applicability for patients with imatinib resistance, but the drugs may also be useful at earlier stages of CML. As noted, in most patients treated with imatinib, CML is well controlled but not eradicated. The molecular basis of persistent disease is poorly understood, but BCR-ABL kinase mutations appear not to be a major factor. Given that the greatest protection from relapse occurs in patients with reductions of 3 log10 or greater in BCR-ABL transcript levels, it may be possible to achieve this goal in more patients with more potent inhibitors. Another strategy for reaching the 3-log10 end point or preventing resistance is to combine inhibitors; preclinical data support this approach.12 The value of combination treatment will depend on any increase in adverse events and the development of resistance. For example, if T315I mutant clones are prevalent, it would be necessary to add a T315I inhibitor to combination therapy. Regardless, the good news for patients with CML is that the long-term prospects for control of the disease are excellent.
These drugs were developed rapidly. A driving factor was the high quality of the basic science associated with clinical trials in CML. Mechanisms of relapse were rapidly identified, and the solution to the crystal structure of ABL in complex with imatinib prompted rapid modification of the structure of the drug. Only a continued investment in a basic understanding of disease mechanisms will make possible similar advances.
It would be logical to ask why two large pharmaceutical companies would have an interest in a disease that affects fewer than 5000 patients per year in the United States — and one in which drug resistance is relatively uncommon. One reason is that imatinib had gross sales of $2.1 billion in 2004. Although this volume of sales is not entirely attributable to its use in CML, it does mean that CML therapy is an attractive market. An encouraging thought is that some large pharmaceutical companies recognize the power of genomic medicine. They have an interest in testing a drug in a small, molecularly defined population, such as patients with imatinib-resistant CML. By limiting testing to a population with a high probability of having a response to therapy, the company reduces the risk of drug failure, and the number of patients who are required to demonstrate clinical activity of the drug can be relatively small. These two factors minimize the costs of drug development, could lead to rapid approval by the Food and Drug Administration, and might result in decreased drug costs.
Dr. Druker has served as a scientific consultant to several biotechnology and pharmaceutical companies concerning kinase inhibitors. His institution is the site of clinical trials sponsored by Novartis and Bristol-Myers Squibb, but neither he nor his laboratory receives funds from these companies. Dr. Druker receives income from a patent on mutated ABL kinase domains, held by Oregon Health and Science University. No other potential conflict of interest relevant to this article was reported.
Source Information
From the Howard Hughes Medical Institute, Oregon Health and Science University Cancer Institute, Portland, Oreg.
References
Druker BJ. Imatinib as a paradigm of targeted therapies. Adv Cancer Res 2004;91:1-30.
Kantarjian H, Giles F, Wunderle L, et al. Nilotinib in imatinib-resistant CML and Philadelphia chromosome-positive ALL. N Engl J Med 2006;354:2542-2551.
Talpaz M, Neil NP, Kantarjian H, et al. Dasatinib in imatinib-resistant Philadelphia chromosome-positive leukemias. N Engl J Med 2006;354:2531-2541.
Druker BJ, Talpaz M, Resta D, et al. Efficacy and safety of a specific inhibitor of the Bcr-Abl tyrosine kinase in chronic myeloid leukemia. N Engl J Med 2001;344:1031-1037.
O'Brien SG, Guilhot F, Larson RA, et al. Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med 2003;348:994-1004.
Simonsson B. Beneficial effects of cytogenetic and molecular response on long-term outcome in patients with newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP) treated with imatinib (IM): update from the IRIS study. Blood 2005;106:52a-52a.
Shah NP, Nicoll JM, Nagar B, et al. Multiple BCR-ABL kinase domain mutations confer polyclonal resistance to the tyrosine kinase inhibitor imatinib (STI571) in chronic phase and blast crisis chronic myeloid leukemia. Cancer Cell 2002;2:117-125.
Schindler T, Bornmann W, Pellicena P, Miller WT, Clarkson B, Kuriyan J. Structural mechanism for STI-571 inhibition of abelson tyrosine kinase. Science 2000;289:1938-1942.
Weisberg E, Manley PW, Breitenstein W, et al. Characterization of AMN107, a selective inhibitor of native and mutant Bcr-Abl. Cancer Cell 2005;7:129-141.
La Rosee P, Corbin AS, Stoffregen EP, Deininger MW, Druker BJ. Activity of the Bcr-Abl kinase inhibitor PD180970 against clinically relevant Bcr-Abl isoforms that cause resistance to imatinib mesylate (Gleevec, STI571). Cancer Res 2002;62:7149-7153.
Shah NP, Tran C, Lee FY, Chen P, Norris D, Sawyers CL. Overriding imatinib resistance with a novel ABL kinase inhibitor. Science 2004;305:399-401.
O'Hare T, Walters DK, Stoffregen EP, et al. Combined Abl inhibitor therapy for minimizing drug resistance in chronic myeloid leukemia: Src/Abl inhibitors are compatible with imatinib. Clin Cancer Res 2005;11:6987-6993.(Brian J. Druker, M.D.)
The success of imatinib as a treatment for CML can be attributed to the critical role of the BCR-ABL tyrosine kinase in causing the disease and the specificity of imatinib as an ABL kinase inhibitor.1 The clinical activity of imatinib is highest in patients with chronic-phase CML.4,5 Although the response rate in patients with accelerated-phase or blast-phase disease is quite high, most such patients have a relapse. Ninety-five percent of patients are in chronic phase at diagnosis; in these patients who are treated with imatinib, blood counts will return to normal in 98 percent, and in 86 percent the Philadelphia chromosome will disappear — in other words, they will have a complete cytogenetic response. With a median follow-up of 54 months, the overall relapse rate for patients with newly diagnosed chronic-phase CML who were treated with imatinib was 16 percent, but for patients with a complete cytogenetic response, the relapse rate was 7 percent.6 Among patients in whom BCR-ABL messenager RNA (mRNA) levels were reduced by at least 3 log, the relapse rate at 54 months was only 3 percent, and none of these patients had progression to the accelerated phase or blast crisis.
If imatinib is performing so well, why are new drugs needed? One reason is that patients in relapse urgently need new therapies. Furthermore, it is not clear that the apparent trend of decreasing relapse rates over time will persist, and even if it does, the absolute number of patients who have a relapse will increase over time. And even though most patients who are treated with imatinib achieve a 3-log reduction in leukemic-cell burden, BCR-ABL transcripts are undetectable in only a few; in most of these patients, moreover, the disease recurs if imatinib is discontinued. Thus, even patients with well-controlled disease have a reservoir of leukemic cells from which relapse may occur.
Studies of patients in relapse have shown that mutations in the kinase domain of BCR-ABL are the predominant mechanism underlying acquired drug resistance to imatinib; another mechanism in some patients is amplification of the BCR-ABL fusion gene.7 Mutations have been observed to affect at least 25 amino acids scattered throughout the ABL kinase domain, and each of them reduces the sensitivity of the kinase to imatinib.
Structural biology has made major contributions to the understanding of imatinib resistance and the design of new inhibitors. The crystal structure of ABL in a complex with imatinib shows that imatinib binds to a unique, inactive conformation of the ABL kinase domain in which the activation loop is in a closed position.8 Mutations that confer resistance to imatinib affect residues that are directly involved in drug binding, that impair the ability of the kinase domain to undergo the extensive conformational changes required for imatinib binding, or that favor the active conformation of the kinase to which imatinib is unable to bind.
Information from the crystal structure suggested two approaches for the circumventing of resistance. One avenue was the modification of imatinib in such a way that the drug binds more tightly to the ABL kinase. This modification was accomplished by chemists at Novartis in the design of nilotinib.9 A second approach was the development of a compound with an entirely different chemical scaffold. This tack, taken by scientists at Bristol-Myers Squibb, was based on the finding that SRC inhibitors also inhibit the wild-type ABL kinase and most imatinib-resistant mutations.10 (SRC is a protein tyrosine kinase that acts as a signal transducer in several molecular pathways within the cell.) Thus, dasatinib, originally synthesized as a SRC-family inhibitor, was tested for its ability to inhibit ABL and imatinib-resistant mutations.11 Both nilotinib and dasatinib are more potent ABL inhibitors than is imatinib and inhibit all tested imatinib-resistant mutations except T315I.
Consistent with the preclinical profiles of nilotinib and dasatinib, responses in the phase 1 trials of these drugs were seen in patients with all imatinib-resistant mutations except T315I.2,3 Responses were also seen in patients with resistance that was not caused by mutations, a finding that may relate to the high potency of these drugs. Both drugs have unique side effects, including pleural effusions with dasatinib and elevated liver enzyme levels and a prolongation of corrected QT intervals with nilotinib. The question as to whether additional side effects will be observed over time will require larger studies and longer follow-up. Response rates in patients with chronic-phase CML were impressive and have thus far been durable, but responses in accelerated-phase and blast-phase disease were lower, and relapses have been common. For this reason, other strategies are required for the advanced phases of CML and for patients with the T315I ABL mutation.
Nilotinib and dasatinib have immediate applicability for patients with imatinib resistance, but the drugs may also be useful at earlier stages of CML. As noted, in most patients treated with imatinib, CML is well controlled but not eradicated. The molecular basis of persistent disease is poorly understood, but BCR-ABL kinase mutations appear not to be a major factor. Given that the greatest protection from relapse occurs in patients with reductions of 3 log10 or greater in BCR-ABL transcript levels, it may be possible to achieve this goal in more patients with more potent inhibitors. Another strategy for reaching the 3-log10 end point or preventing resistance is to combine inhibitors; preclinical data support this approach.12 The value of combination treatment will depend on any increase in adverse events and the development of resistance. For example, if T315I mutant clones are prevalent, it would be necessary to add a T315I inhibitor to combination therapy. Regardless, the good news for patients with CML is that the long-term prospects for control of the disease are excellent.
These drugs were developed rapidly. A driving factor was the high quality of the basic science associated with clinical trials in CML. Mechanisms of relapse were rapidly identified, and the solution to the crystal structure of ABL in complex with imatinib prompted rapid modification of the structure of the drug. Only a continued investment in a basic understanding of disease mechanisms will make possible similar advances.
It would be logical to ask why two large pharmaceutical companies would have an interest in a disease that affects fewer than 5000 patients per year in the United States — and one in which drug resistance is relatively uncommon. One reason is that imatinib had gross sales of $2.1 billion in 2004. Although this volume of sales is not entirely attributable to its use in CML, it does mean that CML therapy is an attractive market. An encouraging thought is that some large pharmaceutical companies recognize the power of genomic medicine. They have an interest in testing a drug in a small, molecularly defined population, such as patients with imatinib-resistant CML. By limiting testing to a population with a high probability of having a response to therapy, the company reduces the risk of drug failure, and the number of patients who are required to demonstrate clinical activity of the drug can be relatively small. These two factors minimize the costs of drug development, could lead to rapid approval by the Food and Drug Administration, and might result in decreased drug costs.
Dr. Druker has served as a scientific consultant to several biotechnology and pharmaceutical companies concerning kinase inhibitors. His institution is the site of clinical trials sponsored by Novartis and Bristol-Myers Squibb, but neither he nor his laboratory receives funds from these companies. Dr. Druker receives income from a patent on mutated ABL kinase domains, held by Oregon Health and Science University. No other potential conflict of interest relevant to this article was reported.
Source Information
From the Howard Hughes Medical Institute, Oregon Health and Science University Cancer Institute, Portland, Oreg.
References
Druker BJ. Imatinib as a paradigm of targeted therapies. Adv Cancer Res 2004;91:1-30.
Kantarjian H, Giles F, Wunderle L, et al. Nilotinib in imatinib-resistant CML and Philadelphia chromosome-positive ALL. N Engl J Med 2006;354:2542-2551.
Talpaz M, Neil NP, Kantarjian H, et al. Dasatinib in imatinib-resistant Philadelphia chromosome-positive leukemias. N Engl J Med 2006;354:2531-2541.
Druker BJ, Talpaz M, Resta D, et al. Efficacy and safety of a specific inhibitor of the Bcr-Abl tyrosine kinase in chronic myeloid leukemia. N Engl J Med 2001;344:1031-1037.
O'Brien SG, Guilhot F, Larson RA, et al. Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med 2003;348:994-1004.
Simonsson B. Beneficial effects of cytogenetic and molecular response on long-term outcome in patients with newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP) treated with imatinib (IM): update from the IRIS study. Blood 2005;106:52a-52a.
Shah NP, Nicoll JM, Nagar B, et al. Multiple BCR-ABL kinase domain mutations confer polyclonal resistance to the tyrosine kinase inhibitor imatinib (STI571) in chronic phase and blast crisis chronic myeloid leukemia. Cancer Cell 2002;2:117-125.
Schindler T, Bornmann W, Pellicena P, Miller WT, Clarkson B, Kuriyan J. Structural mechanism for STI-571 inhibition of abelson tyrosine kinase. Science 2000;289:1938-1942.
Weisberg E, Manley PW, Breitenstein W, et al. Characterization of AMN107, a selective inhibitor of native and mutant Bcr-Abl. Cancer Cell 2005;7:129-141.
La Rosee P, Corbin AS, Stoffregen EP, Deininger MW, Druker BJ. Activity of the Bcr-Abl kinase inhibitor PD180970 against clinically relevant Bcr-Abl isoforms that cause resistance to imatinib mesylate (Gleevec, STI571). Cancer Res 2002;62:7149-7153.
Shah NP, Tran C, Lee FY, Chen P, Norris D, Sawyers CL. Overriding imatinib resistance with a novel ABL kinase inhibitor. Science 2004;305:399-401.
O'Hare T, Walters DK, Stoffregen EP, et al. Combined Abl inhibitor therapy for minimizing drug resistance in chronic myeloid leukemia: Src/Abl inhibitors are compatible with imatinib. Clin Cancer Res 2005;11:6987-6993.(Brian J. Druker, M.D.)