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mTOR and Mitogen-Activated Protein Kinase Pathways in Lung Cancer Therapy
TARGETED THERAPIES SUPPLEMENT
The Akt/mTOR and Mitogen-Activated Protein Kinase Pathways in Lung Cancer Therapy Vassiliki Papadimitrakopoulou, MD,* and Alex A. Adjei, MD, PhD†
Aberrant intracellular signaling resulting from mutations and oncogenic activation, as well as gene amplification of critical proteins involved in signal transduction pathways, are key features of lung cancer. Three important intracellular signaling proteins, the mammalian target of rapamycin, protein kinase B, and mitogen-activated protein kinase kinase have emerged as attractive targets for lung cancer therapy. We review current information on the therapeutic manipulation of these targets and describe early clinical data in lung cancer. (J Thorac Oncol. 2006;1: 749–751)
L
ung cancer is the most common cause of cancer death in the United States, with an estimated annual mortality of more than 160,000.1 Most patients with lung cancer are not cured, and the overall 5-year survival rate is approximately 16%.1 Most patients with non-small cell lung cancer (NSCLC) develop metastatic disease and require systemic therapy, with the most effective current therapy being a combination of chemotherapy and bevacizumab. Unfortunately, the median survival of patients with metastatic NSCLC is 12 months, with a 1-year survival of approximately 35%. This dismal outlook for patients with advanced lung cancer despite the best available therapy has prompted a search for new therapeutic agents. Intracellular signaling inhibitors, with their ability to abrogate dysregulated signaling networks in lung cancer, are particularly attractive because of the theoretical advantage that targeting tumor aberrancy will lead to efficacy with limited toxicity. There has been considerable focus on the Ras-MAPK pathway, as well as the PI3-Kinase/Akt/ mTOR pathway.
THE EXTRACELLULAR SIGNAL-REGULATED KINASE SIGNALING PATHWAY Multicellular organisms have three well-characterized subfamilies of mitogen-activated protein kinases (MAPKs) *MD Anderson Cancer Center, Houston, Texas; †Mayo Clinic and Foundation, Rochester, Minnesota. Address for correspondence: Vassiliki Papadimitrakopoulou, MD, The University of Texas/MD Anderson Cancer Center, Department of Thoracic/ Head and Neck Medical Oncology, 1515 Holcombe Boulevard, Unit 432, Houston, TX 77030. E-mail: [email protected] Copyright © 2006 by the International Association for the Study of Lung Cancer ISSN: 1556-0864/06/0107-0749
that control a vast array of physiological processes. These enzymes are regulated by a characteristic phospho-relay system, in which a series of three protein kinases phosphorylate and activate one another. The extracellular signal-regulated kinases (ERKs), which function in the control of cell division, have been the most studied for cancer therapeutics. It has been shown that inappropriate activation of the MAP kinase pathway, through mutations in upstream proteins introduced via oncogenes, is a feature of many neoplasms, including lung cancer. Mitogen-activated protein kinase kinase (MEK) inhibitors are therefore rational agents for cancer therapy.
Mutations Upstream of MEK Ras There are three well-characterized ras genes encoding three proteins, H-ras, N-ras, and the alternatively spliced K-ras, in mammalian systems. Mutations in these genes are oncogenic. Mutations in NSCLC are found only in the K-ras gene, with a frequency of approximately 40% in adenocarcinomas. Recent emerging data suggest that in NSCLC, K-ras mutations may be particularly common in tumors from smokers, with a frequency of almost 70%.2
Raf The potential role of Raf kinase in carcinogenesis has been recognized recently, with the description of activating mutations of B-Raf in approximately 70% of melanomas and in a number of other human tumor types, including ovarian and papillary thyroid carcinomas.3 This activating B-Raf allele can be detected, allowing tumor genotyping in the clinical setting. The activating mutations in K-ras and B-raf represent the first report of a tandem activating mutation in the same signaling pathway. Whereas the frequency of B-raf mutations in NSCLC is approximately 5%, taken together with K-ras, one or the other of these mutations may be present in approximately 50% of NSCLCs. Tumors such as NSCLC, which possess either K-ras or B-raf mutations or overexpression of receptors that signal through the rasMAPK pathway such as EGFR, may be amenable to inhibition of the downstream protein MEK. Thus, clearly, inhibition of MEK is an appealing approach to lung cancer therapy
MEK Inhibitors The only known substrate for MEK is MAP kinase (MAPK). Sequential activation of MEK and MAPK (also known as extracellular-related kinase or ERK) classically occurs downstream of, but can be independent of, ras and raf.
Journal of Thoracic Oncology • Volume 1, Number 7, September 2006
749
Papadimitrakopoulou and Adjei
Journal of Thoracic Oncology • Volume 1, Number 7, September 2006
MAPK phosphorylation results in the activation of processes such as anchorage-independent growth, cell cycle progression from G1 to S phase, gene transcription, phenotype transformation, and cytoskeletal changes involving spindle assembly, as in meiosis and mitosis.4 PD-184352, also known as CI-1040, is an orally active difluorobenzamide that exhibited highly selective, nanomolar inhibition of MEK in preclinical studies and was the first MEK inhibitor to be tested in the clinic.5 In completed phase I studies, the major toxicities were diarrhea, fatigue, nausea, and, rarely, skin rash. The recommended phase II dose was 800 mg by mouth twice daily. One partial response in a patient with pancreatic cancer was documented, and 25% of patients (including three with NSCLC) achieved disease stabilization for 4 months or longer.6 Based on these promising findings, a broad phase II study was performed in patients with breast, pancreatic, colorectal, and NSCLC. Eighteen patients with NSCLC previously treated with one systemic chemotherapy regimen were enrolled. No objective responses were documented in these 18 patients. Three patients maintained disease stability for 3, 3, and 10 months, respectively. The median time to progression was 4.2 months, and median survival was 5.2 months.7 Interestingly, 70% of NSCLC tumor samples overexpressed p-ERK at baseline, indicating that the MEK pathway is activated in these tumors. In parallel pharmacokinetic studies, it was demonstrated that there is up to a 100-fold variation in CI-1040 exposure in different patients. Thus, poor pharmacokinetics was believed to have contributed to the lack of efficacy of CI-1040 in phase II studies. Based on this, and because of the documented activation of the MEK pathway in NSCLC, MEK is still believed to be a valid target for lung cancer therapy. Phase I studies of two second-generation MEK inhibitors, PD0325901 and ARRY-142886 (AZD6244) are ongoing, with full reports being eagerly awaited.
Akt/mTOR The PI-3 kinase (PI3K)/Akt signaling represents a major cell survival pathway. Its activation has long been associated with malignant transformation and apoptotic resistance. It is generally thought that the mammalian target of rapamycin (mTOR) functions downstream of the PI3K/Akt pathway and many other signaling molecules often deregulated in cancer cells, such as EGFR, HER2, IGF-1R, PTEN, TSC1/2, Ras, Raf, Abl and the estrogen receptor, and it is negatively regulated by LKB1, a serine/threonine kinase with tumor suppressor activity. mTOR is a central controller of cell growth, cell division, and protein translation, primarily through two distinct pathways: ribosomal p70 S6 kinase (p70S6K) and the eukaryotic translation initiation factor 4E (eIF4E) binding proteins (4E-BPs). This pathway is frequently altered in cancer either through inactivating mutations of the LKB1 or constitutive activation of signaling of PI3K/Akt. Frequent Akt activation and mTOR phosphorylation were found in 51% of NSCLC patient samples and in 74% of NSCLC cell lines,8 and the PI3K/Akt/mTOR pathway has been shown to be important in NSCLC oncogenesis.9 Similar work has demonstrated that elevated PI3 kinase/Akt
750
activity not only is common in NSCLC but also promotes the survival of cancer cells in NSCLC.10 Notably, pharmacologic inhibition of PI3 kinase leads to proliferative arrest in NSCLC cell lines.11 Similarly, in vitro studies have demonstrated that inhibition of Akt activity, by pharmacologic or genetic means, greatly improves the cellular response to treatment modalities often used to treat NSCLC, such as chemotherapy and radiation.10
mTOR Inhibitors Several mTOR inhibitors are currently under development: rapamycin and its derivatives CCI-770 and RAD001, as well as AP23573. mTOR inhibitors are active in preclinical models of human lung cancer with direct inhibition of tumor growth and suppression of angiogenesis.12 Sensitivity to mTOR inhibition with RAD001 in tumor cells correlates directly with the level of activated AKT.13 RAD001, an orally bioavailable agent, inhibits proliferation of numerous cancer cell lines and xenografts and causes prolonged inactivation of p70s6k in tumor cells (at least 72 hours). It also possesses antiangiogenic activity and exhibits an additive effect when combined with cytotoxic agents (paclitaxel, doxorubicin, cisplatinum, and gemcitabine). As reported by Khuri et al.,14 mTOR inhibition by rapamycin triggers rapid and sustained activation of PI3K/ Akt survival pathway in human lung and other types of cancer cells, such that the combination of mTOR targeted therapy with drugs that block PI3K/Akt activation might also be reasonable. The drug was well tolerated in phase I studies; common adverse events were rash and stomatitis in approximately 40% (grade 3 in only 1% and 5% of patients, respectively) of the patients.15,16 Dose-limiting toxicities were stomatitis, neutropenia, and hypoglycemia. Pharmacodynamic studies based on inhibition of pS6kinase and safety profile support a phase II dosage of 10 mg/day or 50 to 70 mg/week. In addition, reliable biomarkers of drug activity have been indicated as pS6K and p-eIF4G.16 Tumor response and prolonged disease stabilization have been observed, notably in NSCLC. In addition, clinical responses have been reported in patients with NSCLC treated with a rapamycin, CCI779, or AP23573. In lung and other cancers that overexpress EGFR, resistance to EGFR-targeted therapies may involve activation of alternative signaling pathways that activate Akt and maintain signaling through TOR.17 Combined inhibition of EGFR and mTOR signaling enhanced in vivo anti-tumor activity in a glioblastoma multiforme model.18 The rational combination of mTOR inhibition and EGFR tyrosine kinase inhibition has been pursued in at least two clinical studies. The first used a combination of gefitinib with RAD001. Among the 10 patients treated and reported to date, two patients experienced PR; notably, both were male smokers without demonstrated mutations of the EGFR tyrosine kinase domain,19 two features that do not predict gefitinib responsiveness. Toxicity consisted of stomatitis, lymphopenia, thrombocytopenia, fatigue, hypertriglyceridemia, and rash. The second ongoing
Copyright © 2006 by the International Association for the Study of Lung Cancer
Journal of Thoracic Oncology • Volume 1, Number 7, September 2006
study uses a combination of erlotinib and RAD001. Early results are encouraging.
10.
SUMMARY In conclusion, the approaches we described for targeting signaling pathways have shown preliminary evidence of activity and feasibility. Clinical trials using combinations of these agents with standard chemotherapy and other signaling inhibitors (based on hints provided by preclinical studies) are desired and are being planned.
11.
12. 13.
REFERENCES 1. Jemal A, Siegel R, Ward E, et al. Cancer statistics, 2006. CA Cancer J Clin 2006;56:106–130. 2. Friday BB, Adjei AA. K-ras as a target for cancer therapy. Biochim Biophys Acta 2006;1756:127–144. 3. Davies H, Bignell GR, Cox C, et al. Mutations of the BRAF gene in human cancer. Nature 2002;417:949–954. 4. Adjei AA. Signal transduction pathway targets for anticancer drug discovery. Curr Pharm Des 2000;6:362–378. 5. Sebolt-Leopold JS, Dudley DT, Herrera R, et al. Blockade of the MAP kinase pathway suppresses growth of colon tumors in vivo. Nature Med 1999;5:810–816. 6. Lorusso PM, Adjei AA, Varterasian M, et al. Phase I and pharmacodynamic study of the oral MEK inhibitor CI-1040 in patients with advanced malignancies. J Clin Oncol 2006;23:5281–5293. 7. Rinehart J, Adjei AA, Lorusso PM, et al. Multicenter phase II study of the oral MEK inhibitor, CI-1040, in patients with advanced non-smallcell lung, breast, colon, and pancreatic cancer. J Clin Oncol 2004;22: 4456–4462. 8. Balsara BR, Pei J, Mitsuuchi Y, et al. Frequent activation of AKT in snmall-cell lung carcinomas and preneoplastic bronchial lesions. Carcinogenesis 2004;25:2053–2059. 9. West KA, Linnoila IR, Belinsky SA, et al. Tobacco carcinogen-induced
14. 15.
16.
17. 18. 19.
Akt/mTOR and MAP Kinase Pathways in Lung Cancer
cellular transformation increases activation of the phosphatidyl 3=kinase/Akt pathway in vitro and in vivo. Cancer Res 2004;64:446–451. Brognard J, Clark AS, Yi Y, et al. Akt is constitutively active in non-small cell lung cancer cells and promotes cellular survival and resistance to chemotherapy and radiation. Cancer Res 2001;61:3986– 3997. Lee H-Y, Srinivas H, Xia D, et al. Evidence that phosphatidyl 3=-kinaseand mitogen-activated protein kinase kinase-4/c-Jun NH2-terminal kinase-dependent pathways cooperate to maintain lung cancer survival. J Biol Chem 2003;278:23630–23638. Boffa DJ, Luan F, Thomas D, et al. Rapamycin inhibits the growth and metastatic progression of non-small cell lung cancer. Clin Cancer Res 2004;10:293–300. Boulay A, Zumstein-Mecker S, Stephan C, et al. Antitumor efficacy of intermittent treatment schedules with the rapamycin derivative RAD001 correlates with prolonged inactivation of ribosomal protein S6 kinase 1 in peripheral blood mononuclear cells. Cancer Res 2004;54:252–261. Sun SY, Rosenberg LM, Wang X, et al. Activation of Akt and eIF4E survival pathways by rapamycin-mediated mammalian target of rapamycin inhibition. Cancer Res 2006;65:7052–7058. O’Donnell A, Faivre S, Judson I, et al. A phase I study of the oral mTOR inhibitor RAD001 as monotherapy to identify the optimal biologically effective dose using toxicity, pharmacokinetic and pharmacodynamic endpoints in patients with solid tumors (Abstract). Proc Am Soc Clin Oncol 2003;22:200. Tabernero J, Rojo F, Burris H, et al. A phase I study with tumor molecular pharmacodynamic (MPD) evaluation of dose and schedule of the oral m-TOR-inhibitor everolimus ( RAD001) in patients (pts) with advanced solid tumors (Abstract). Proc Am Soc Clin Oncol 2006;23:193. Johnson DH, Arteaga CL. Gefitinib in recurrent non-small-cell lung cancer: an IDEAl trial? J Clin Oncol 2003;21:2227–2229. Li B, Chang CM, Yuan M, et al. Resistance to small molecule inhibitors of epidermal growth factor receptor in malignant gliomas. Cancer Res 2003;63:7443–7450. Milton DT, Kris MG, Azzoli CG, et al. Phase I/II trial of concurrent gefitinib and RAD001 (Everolimus) in patients with advanced non-small cell lung cancer: preliminary results (Abstract). Proc Am Soc Clin Oncol 2006 23:646.
Copyright © 2006 by the International Association for the Study of Lung Cancer
751
The Akt/mTOR and Mitogen-Activated Protein Kinase Pathways in Lung Cancer Therapy Vassiliki Papadimitrakopoulou, MD,* and Alex A. Adjei, MD, PhD†
Aberrant intracellular signaling resulting from mutations and oncogenic activation, as well as gene amplification of critical proteins involved in signal transduction pathways, are key features of lung cancer. Three important intracellular signaling proteins, the mammalian target of rapamycin, protein kinase B, and mitogen-activated protein kinase kinase have emerged as attractive targets for lung cancer therapy. We review current information on the therapeutic manipulation of these targets and describe early clinical data in lung cancer. (J Thorac Oncol. 2006;1: 749–751)
L
ung cancer is the most common cause of cancer death in the United States, with an estimated annual mortality of more than 160,000.1 Most patients with lung cancer are not cured, and the overall 5-year survival rate is approximately 16%.1 Most patients with non-small cell lung cancer (NSCLC) develop metastatic disease and require systemic therapy, with the most effective current therapy being a combination of chemotherapy and bevacizumab. Unfortunately, the median survival of patients with metastatic NSCLC is 12 months, with a 1-year survival of approximately 35%. This dismal outlook for patients with advanced lung cancer despite the best available therapy has prompted a search for new therapeutic agents. Intracellular signaling inhibitors, with their ability to abrogate dysregulated signaling networks in lung cancer, are particularly attractive because of the theoretical advantage that targeting tumor aberrancy will lead to efficacy with limited toxicity. There has been considerable focus on the Ras-MAPK pathway, as well as the PI3-Kinase/Akt/ mTOR pathway.
THE EXTRACELLULAR SIGNAL-REGULATED KINASE SIGNALING PATHWAY Multicellular organisms have three well-characterized subfamilies of mitogen-activated protein kinases (MAPKs) *MD Anderson Cancer Center, Houston, Texas; †Mayo Clinic and Foundation, Rochester, Minnesota. Address for correspondence: Vassiliki Papadimitrakopoulou, MD, The University of Texas/MD Anderson Cancer Center, Department of Thoracic/ Head and Neck Medical Oncology, 1515 Holcombe Boulevard, Unit 432, Houston, TX 77030. E-mail: [email protected] Copyright © 2006 by the International Association for the Study of Lung Cancer ISSN: 1556-0864/06/0107-0749
that control a vast array of physiological processes. These enzymes are regulated by a characteristic phospho-relay system, in which a series of three protein kinases phosphorylate and activate one another. The extracellular signal-regulated kinases (ERKs), which function in the control of cell division, have been the most studied for cancer therapeutics. It has been shown that inappropriate activation of the MAP kinase pathway, through mutations in upstream proteins introduced via oncogenes, is a feature of many neoplasms, including lung cancer. Mitogen-activated protein kinase kinase (MEK) inhibitors are therefore rational agents for cancer therapy.
Mutations Upstream of MEK Ras There are three well-characterized ras genes encoding three proteins, H-ras, N-ras, and the alternatively spliced K-ras, in mammalian systems. Mutations in these genes are oncogenic. Mutations in NSCLC are found only in the K-ras gene, with a frequency of approximately 40% in adenocarcinomas. Recent emerging data suggest that in NSCLC, K-ras mutations may be particularly common in tumors from smokers, with a frequency of almost 70%.2
Raf The potential role of Raf kinase in carcinogenesis has been recognized recently, with the description of activating mutations of B-Raf in approximately 70% of melanomas and in a number of other human tumor types, including ovarian and papillary thyroid carcinomas.3 This activating B-Raf allele can be detected, allowing tumor genotyping in the clinical setting. The activating mutations in K-ras and B-raf represent the first report of a tandem activating mutation in the same signaling pathway. Whereas the frequency of B-raf mutations in NSCLC is approximately 5%, taken together with K-ras, one or the other of these mutations may be present in approximately 50% of NSCLCs. Tumors such as NSCLC, which possess either K-ras or B-raf mutations or overexpression of receptors that signal through the rasMAPK pathway such as EGFR, may be amenable to inhibition of the downstream protein MEK. Thus, clearly, inhibition of MEK is an appealing approach to lung cancer therapy
MEK Inhibitors The only known substrate for MEK is MAP kinase (MAPK). Sequential activation of MEK and MAPK (also known as extracellular-related kinase or ERK) classically occurs downstream of, but can be independent of, ras and raf.
Journal of Thoracic Oncology • Volume 1, Number 7, September 2006
749
Papadimitrakopoulou and Adjei
Journal of Thoracic Oncology • Volume 1, Number 7, September 2006
MAPK phosphorylation results in the activation of processes such as anchorage-independent growth, cell cycle progression from G1 to S phase, gene transcription, phenotype transformation, and cytoskeletal changes involving spindle assembly, as in meiosis and mitosis.4 PD-184352, also known as CI-1040, is an orally active difluorobenzamide that exhibited highly selective, nanomolar inhibition of MEK in preclinical studies and was the first MEK inhibitor to be tested in the clinic.5 In completed phase I studies, the major toxicities were diarrhea, fatigue, nausea, and, rarely, skin rash. The recommended phase II dose was 800 mg by mouth twice daily. One partial response in a patient with pancreatic cancer was documented, and 25% of patients (including three with NSCLC) achieved disease stabilization for 4 months or longer.6 Based on these promising findings, a broad phase II study was performed in patients with breast, pancreatic, colorectal, and NSCLC. Eighteen patients with NSCLC previously treated with one systemic chemotherapy regimen were enrolled. No objective responses were documented in these 18 patients. Three patients maintained disease stability for 3, 3, and 10 months, respectively. The median time to progression was 4.2 months, and median survival was 5.2 months.7 Interestingly, 70% of NSCLC tumor samples overexpressed p-ERK at baseline, indicating that the MEK pathway is activated in these tumors. In parallel pharmacokinetic studies, it was demonstrated that there is up to a 100-fold variation in CI-1040 exposure in different patients. Thus, poor pharmacokinetics was believed to have contributed to the lack of efficacy of CI-1040 in phase II studies. Based on this, and because of the documented activation of the MEK pathway in NSCLC, MEK is still believed to be a valid target for lung cancer therapy. Phase I studies of two second-generation MEK inhibitors, PD0325901 and ARRY-142886 (AZD6244) are ongoing, with full reports being eagerly awaited.
Akt/mTOR The PI-3 kinase (PI3K)/Akt signaling represents a major cell survival pathway. Its activation has long been associated with malignant transformation and apoptotic resistance. It is generally thought that the mammalian target of rapamycin (mTOR) functions downstream of the PI3K/Akt pathway and many other signaling molecules often deregulated in cancer cells, such as EGFR, HER2, IGF-1R, PTEN, TSC1/2, Ras, Raf, Abl and the estrogen receptor, and it is negatively regulated by LKB1, a serine/threonine kinase with tumor suppressor activity. mTOR is a central controller of cell growth, cell division, and protein translation, primarily through two distinct pathways: ribosomal p70 S6 kinase (p70S6K) and the eukaryotic translation initiation factor 4E (eIF4E) binding proteins (4E-BPs). This pathway is frequently altered in cancer either through inactivating mutations of the LKB1 or constitutive activation of signaling of PI3K/Akt. Frequent Akt activation and mTOR phosphorylation were found in 51% of NSCLC patient samples and in 74% of NSCLC cell lines,8 and the PI3K/Akt/mTOR pathway has been shown to be important in NSCLC oncogenesis.9 Similar work has demonstrated that elevated PI3 kinase/Akt
750
activity not only is common in NSCLC but also promotes the survival of cancer cells in NSCLC.10 Notably, pharmacologic inhibition of PI3 kinase leads to proliferative arrest in NSCLC cell lines.11 Similarly, in vitro studies have demonstrated that inhibition of Akt activity, by pharmacologic or genetic means, greatly improves the cellular response to treatment modalities often used to treat NSCLC, such as chemotherapy and radiation.10
mTOR Inhibitors Several mTOR inhibitors are currently under development: rapamycin and its derivatives CCI-770 and RAD001, as well as AP23573. mTOR inhibitors are active in preclinical models of human lung cancer with direct inhibition of tumor growth and suppression of angiogenesis.12 Sensitivity to mTOR inhibition with RAD001 in tumor cells correlates directly with the level of activated AKT.13 RAD001, an orally bioavailable agent, inhibits proliferation of numerous cancer cell lines and xenografts and causes prolonged inactivation of p70s6k in tumor cells (at least 72 hours). It also possesses antiangiogenic activity and exhibits an additive effect when combined with cytotoxic agents (paclitaxel, doxorubicin, cisplatinum, and gemcitabine). As reported by Khuri et al.,14 mTOR inhibition by rapamycin triggers rapid and sustained activation of PI3K/ Akt survival pathway in human lung and other types of cancer cells, such that the combination of mTOR targeted therapy with drugs that block PI3K/Akt activation might also be reasonable. The drug was well tolerated in phase I studies; common adverse events were rash and stomatitis in approximately 40% (grade 3 in only 1% and 5% of patients, respectively) of the patients.15,16 Dose-limiting toxicities were stomatitis, neutropenia, and hypoglycemia. Pharmacodynamic studies based on inhibition of pS6kinase and safety profile support a phase II dosage of 10 mg/day or 50 to 70 mg/week. In addition, reliable biomarkers of drug activity have been indicated as pS6K and p-eIF4G.16 Tumor response and prolonged disease stabilization have been observed, notably in NSCLC. In addition, clinical responses have been reported in patients with NSCLC treated with a rapamycin, CCI779, or AP23573. In lung and other cancers that overexpress EGFR, resistance to EGFR-targeted therapies may involve activation of alternative signaling pathways that activate Akt and maintain signaling through TOR.17 Combined inhibition of EGFR and mTOR signaling enhanced in vivo anti-tumor activity in a glioblastoma multiforme model.18 The rational combination of mTOR inhibition and EGFR tyrosine kinase inhibition has been pursued in at least two clinical studies. The first used a combination of gefitinib with RAD001. Among the 10 patients treated and reported to date, two patients experienced PR; notably, both were male smokers without demonstrated mutations of the EGFR tyrosine kinase domain,19 two features that do not predict gefitinib responsiveness. Toxicity consisted of stomatitis, lymphopenia, thrombocytopenia, fatigue, hypertriglyceridemia, and rash. The second ongoing
Copyright © 2006 by the International Association for the Study of Lung Cancer
Journal of Thoracic Oncology • Volume 1, Number 7, September 2006
study uses a combination of erlotinib and RAD001. Early results are encouraging.
10.
SUMMARY In conclusion, the approaches we described for targeting signaling pathways have shown preliminary evidence of activity and feasibility. Clinical trials using combinations of these agents with standard chemotherapy and other signaling inhibitors (based on hints provided by preclinical studies) are desired and are being planned.
11.
12. 13.
REFERENCES 1. Jemal A, Siegel R, Ward E, et al. Cancer statistics, 2006. CA Cancer J Clin 2006;56:106–130. 2. Friday BB, Adjei AA. K-ras as a target for cancer therapy. Biochim Biophys Acta 2006;1756:127–144. 3. Davies H, Bignell GR, Cox C, et al. Mutations of the BRAF gene in human cancer. Nature 2002;417:949–954. 4. Adjei AA. Signal transduction pathway targets for anticancer drug discovery. Curr Pharm Des 2000;6:362–378. 5. Sebolt-Leopold JS, Dudley DT, Herrera R, et al. Blockade of the MAP kinase pathway suppresses growth of colon tumors in vivo. Nature Med 1999;5:810–816. 6. Lorusso PM, Adjei AA, Varterasian M, et al. Phase I and pharmacodynamic study of the oral MEK inhibitor CI-1040 in patients with advanced malignancies. J Clin Oncol 2006;23:5281–5293. 7. Rinehart J, Adjei AA, Lorusso PM, et al. Multicenter phase II study of the oral MEK inhibitor, CI-1040, in patients with advanced non-smallcell lung, breast, colon, and pancreatic cancer. J Clin Oncol 2004;22: 4456–4462. 8. Balsara BR, Pei J, Mitsuuchi Y, et al. Frequent activation of AKT in snmall-cell lung carcinomas and preneoplastic bronchial lesions. Carcinogenesis 2004;25:2053–2059. 9. West KA, Linnoila IR, Belinsky SA, et al. Tobacco carcinogen-induced
14. 15.
16.
17. 18. 19.
Akt/mTOR and MAP Kinase Pathways in Lung Cancer
cellular transformation increases activation of the phosphatidyl 3=kinase/Akt pathway in vitro and in vivo. Cancer Res 2004;64:446–451. Brognard J, Clark AS, Yi Y, et al. Akt is constitutively active in non-small cell lung cancer cells and promotes cellular survival and resistance to chemotherapy and radiation. Cancer Res 2001;61:3986– 3997. Lee H-Y, Srinivas H, Xia D, et al. Evidence that phosphatidyl 3=-kinaseand mitogen-activated protein kinase kinase-4/c-Jun NH2-terminal kinase-dependent pathways cooperate to maintain lung cancer survival. J Biol Chem 2003;278:23630–23638. Boffa DJ, Luan F, Thomas D, et al. Rapamycin inhibits the growth and metastatic progression of non-small cell lung cancer. Clin Cancer Res 2004;10:293–300. Boulay A, Zumstein-Mecker S, Stephan C, et al. Antitumor efficacy of intermittent treatment schedules with the rapamycin derivative RAD001 correlates with prolonged inactivation of ribosomal protein S6 kinase 1 in peripheral blood mononuclear cells. Cancer Res 2004;54:252–261. Sun SY, Rosenberg LM, Wang X, et al. Activation of Akt and eIF4E survival pathways by rapamycin-mediated mammalian target of rapamycin inhibition. Cancer Res 2006;65:7052–7058. O’Donnell A, Faivre S, Judson I, et al. A phase I study of the oral mTOR inhibitor RAD001 as monotherapy to identify the optimal biologically effective dose using toxicity, pharmacokinetic and pharmacodynamic endpoints in patients with solid tumors (Abstract). Proc Am Soc Clin Oncol 2003;22:200. Tabernero J, Rojo F, Burris H, et al. A phase I study with tumor molecular pharmacodynamic (MPD) evaluation of dose and schedule of the oral m-TOR-inhibitor everolimus ( RAD001) in patients (pts) with advanced solid tumors (Abstract). Proc Am Soc Clin Oncol 2006;23:193. Johnson DH, Arteaga CL. Gefitinib in recurrent non-small-cell lung cancer: an IDEAl trial? J Clin Oncol 2003;21:2227–2229. Li B, Chang CM, Yuan M, et al. Resistance to small molecule inhibitors of epidermal growth factor receptor in malignant gliomas. Cancer Res 2003;63:7443–7450. Milton DT, Kris MG, Azzoli CG, et al. Phase I/II trial of concurrent gefitinib and RAD001 (Everolimus) in patients with advanced non-small cell lung cancer: preliminary results (Abstract). Proc Am Soc Clin Oncol 2006 23:646.
Copyright © 2006 by the International Association for the Study of Lung Cancer
751