- Email: [email protected]
Autophagy facilitates the Lapatinib resistance of HER2 positive breast cancer cells
Medical Hypotheses 77 (2011) 206–208
Contents lists available at ScienceDirect
Medical Hypotheses journal homepage: www.elsevier.com/locate/mehy
Autophagy facilitates the Lapatinib resistance of HER2 positive breast cancer cells Suning Chen a,1, Xiumin Li b,1, Juan Feng a, Ying Chang a, Zhirui Wang a, Aidong Wen a,⇑ a b
Department of Pharmacy, Xijing Hospital, The Fourth Military Medical University, ChangLe West Road #15, 710032 Xi’an, Shaanxi Province, People’s Republic of China Department of Pharmacy, General Hospital of Beijing Military Region, 100700 Beijing, People’s Republic of China
a r t i c l e
i n f o
Article history: Received 6 January 2011 Accepted 8 April 2011
a b s t r a c t ErbB2 receptor (HER2) tyrosine kinase was overexpressed in about 25% breast cancers, and was correlated with extremely aggressive phenotype and poor prognosis. Lapatinib, an oral, reversible inhibitor of both ErbB2 and EGFR tyrosine kinases, was approved in combination with capecitabine for treating advanced stage ErbB2 positive breast cancers. However, the clinical response of Lapatinib was seriously limited by the drug resistance. We established the Lapatinib resistant breast cancer cell lines and the preliminary data demonstrated the increased autophagosome formation in the stable resistant cells. The resistant cells were re-sensitized to Lapatinib after treated with autophagy inhibitor. According to our preliminary data and related reference, we hypothesized that autophagy could facilitate the ErbB2 positive breast cancer cells to be Lapatinib resistant and promoted the survival of the resistant cells. The abrogation of autophagy might restore the drug sensitivity. Autophagy might be one of the targets to overcome the Lapatinib resistance. Crown Copyright Ó 2011 Published by Elsevier Ltd. All rights reserved.
Introduction Overexpression of the ErbB2 receptor (HER2) tyrosine kinase can be found in about 25% breast cancers, and is associated with extremely aggressive cancer phenotype and worse prognosis [1– 3]. As an oral, reversible inhibitor of both ErbB2 and EGFR tyrosine kinases, Lapatinib (GW572016/Tykerb) was approved in combination with capecitabine for treating the advanced stage ErbB2 positive breast cancers that progressed on prior trastuzumab-based therapies by the FDA in 2007 [4,5]. However, the clinical response of Lapatinib was only about 24% [6,7]. Not all of the ErbB2 positive breast cancer cells responded to Lapatinib treatment, and resistance to Lapatinib developed in some patients and/or tumors during chronic exposure to the drug [8,9]. Since the therapy efficacy of Lapatinib was subjected to the intrinsic and acquired resistance, it is urgent to uncover the potential mechanisms conferring resistance to Lapatinib. Although previous research has provided evidence for possible mechanisms, to date, the reason to induce resistance to Lapatinib is not fully elucidated. For the resistance of trastuzumab, PTEN loss and PIK3CA mutations played an important role. Due to the fact that both Lapatinib and trastuzumab was based on the blocking of ErbB2-PI3K signal pathway [10–12], we cannot eliminate the involvement of PTEN loss and PIK3CA mutation in Lapatinib resistance. Other evidence also showed that increased expression of the membrane receptor tyrosine kinase AXL conferred the resistance to ⇑ Corresponding author. Tel.: +86 29 84773636. 1
E-mail address: [email protected] (A. Wen). These authors contributed equally to this work.
Lapatinib and trastuzumab. The combination with AXL inhibitor could particularly reverse the resistance to Lapatinib [8]. Also, Ras could induce the resistance to Lapatinib and overcame by MEK inhibition [13]. Remarkably, MCL-1, one member of Bcl-2 family, induced the Lapatinib resistance in HCT116 cells and the inhibition of MCL-1 could restore the sensitivity of Lapatinib toxicity via BAK-dependent autophagy [14,15]. However, other mechanisms which induce Lapatinib resistance are not well characterized yet. Autophagy is a cellular catabolic degradation response to stress or metabolic starvation whereby cellular proteins are engulfed, digested and recycled to sustain cellular metabolism [16,17]. The expanding membrane enwraps portions of the cytoplasm and leads to the formation of double-membrane-bound, sequestering vesicles, called autophagosomes, which is the unique character of autophagy. Autophagosomes subsequently fuse with lysosomes and the inner membrane of the autophagosome together with the enclosed cargo is degraded. The resulting macromolecules are released into the cytosol through lysosomal membrane permeases for recycling [18]. There are at least 30 ATG genes involved in autophagosome formation, including Atg1, Atg8 and Atg23 etc. [19]. The basal level of autophagy has an important homeostatic function to maintain the protein and organelle quality control and prevent the accumulation of defective organelles and aggregated proteins [20,21]. However, the role of autophagy in cancer remains controversial [22–25]. Since the loss of the essential autophagy gene such as Becn1 and Atg4C is found frequently in human breast and prostate cancers, it was believed that autophagy had an important role in tumor suppression [26–28]. Paradoxically,
0306-9877/$ - see front matter Crown Copyright Ó 2011 Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.mehy.2011.04.013
S. Chen et al. / Medical Hypotheses 77 (2011) 206–208
more and more data demonstrated that autophagy could protect cancer cells against the metabolic stress including drug resistance [25,29,30]. For example, induced autophagy could facilitate the HER2 positive breast cancer cells to be resistant to herceptin [30,31]. Furthermore, targeting autophagy potentiates tyrosine kinase inhibitor induced cell death in CML stem cells [32]. We established the stable resistant cells to Lapatinib in BT474 HER2 positive breast cancer cell lines. Notably, the autophagosome formation increased a lot in the Lapatinib resistant cells. Combined the literature and our preliminary data, we believed that autophagy might be regarded as an important survival mechanism of the breast cancer cells resistant to Lapatinib. Hypothesis We hypothesized that most of the sensitive cells will be killed during the long-term treatment of Lapatinib to HER2 positive breast cancer cells. But a few cells remain the tolerance to Lapatinib due to the cell’s protective mechanism of autophagy induced by the metabolic stress environment (Fig. 1). So, autophagy can facilitate the acquired Lapatinib resistance of HER2 positive breast cancer cells, which might be one of reasons of tumor recurrence and metastasis. Due to the protection of autophagy from Lapatinib toxicity, the inhibition of the autophagy might restore the drug sensitivity. The autophagy inhibitors such as hydroxychloroquine (HCQ), 3-methyladenine (3-MA) might be helpful to restore the sensitivity of the resistant cells to Lapatinib via abolishing the formation process and degradation ability of autophagosome [33,34]. Alternatively, the abrogation of key molecules to form autophagosome, such as Atg1, Atg8 etc., also might be useful to re-sensitize the Lapatinib treatment. It is promising to expect the autophagy inhibitors to be the next generation drugs to overcome the Lapatinib resistance of HER2 positive breast cancer cells. Hypothesis evaluation and discussion One of the most daunting clinical problems is the frequent relapse of tumors after treatment, mainly due to the drug resistance. Although autophagy was widely reported to be involved in drug resistance [31,35,36], it is not clear whether and how autophagy conferring Lapatinib resistance. Herein, according our hypothesis, there are several key points needed to pay close attention in the following experiment.
Fig. 1. Autophagy facilitates the Lapatinib resistance of HER2 positive breast cancer cells.
207
We detected the increasing autophagosomes formation in the Lapatinib resistant breast cancer cells with transmission electron microscopy, which was currently the golden standard to monitor autophagy in situ [37]. To further validate this hypothesis, we should firstly confirm the activation of autophagic molecules in Lapatinib resistant cells compared with the parental, such as Beclin1, ATG7, LC3-II etc. Secondly, it is critical to identify the function of autophagy in Lapatinib resistant cells through blocking autophagy with the specific inhibitor to abolish the autophagosome formation, such as chloroquine (CQ) and bafilomycin A1 (BA) [31,32]. Also we can use the specific shRNA targeting the key autophagy associated molecules, such as ATG5 and ATG7. If autophagy sustains the cell viability in resistant cells, the block of autophagy will induce the resistant cells much more susceptible to Lapatinib toxicity. However, whether autophagy is a death-induced mechanism or a protective effort for cellular survival is still a controversy. So the autophagy inhibitor might increase the tumor incidence under some circumstance. Undoubtedly, we should pay more attention to the autophagy inhibitor treatment. Finally, it is also very important to clarify the mechanism to induce the autophagy in Lapatinib resistant breast cancer cells. So far, there are several key mechanisms to explain the autophagy generation, such as PI3K-Akt-mTOR, LKB1-AMPK-mTOR, P53 and Beclin1 etc. We need to focus one or more pathway to elucidate the reason of autophagy formation in Lapatinib resistant cells. Since drug resistance is the main challenge for the therapeutic efficacy of Lapatinib, it is very important to explore the possible resistant mechanism. We believe that it will be much more helpful to elucidate the function of autophagy in Lapatinib resistance, and also will provide the potential targets to overcome Lapatinib resistance. Conflicts of interest None declared. References [1] Curigliano G, Viale G, Bagnardi V, Fumagalli L, Locatelli M, Rotmensz N, et al. Clinical relevance of HER2 overexpression/amplification in patients with small tumor size and node-negative breast cancer. J Clin Oncol 2009;27:5693–9. [2] Pommier SJ, Quan GG, Christante D, Muller P, Newell AE, Olson SB, et al. Characterizing the HER2/neu status and metastatic potential of breast cancer stem/progenitor cells. Ann Surg Oncol 2010;17:613–23. [3] Jemal A, Siegel R, Xu J, Ward E. Cancer statistics, 2010. CA Cancer J Clin 2010;60:277–300. [4] Geyer CE, Forster J, Lindquist D, Chan S, Romieu CG, Pienkowski T, et al. Lapatinib plus capecitabine for HER2-positive advanced breast cancer. N Engl J Med 2006;355:2733–43. [5] Macfarlane RJ, Gelmon KA. Lapatinib for breast cancer: a review of the current literature. Expert Opin Drug Saf 2011;10:109–21. [6] Esteva FJ, Yu D, Hung MC, Hortobagyi GN. Molecular predictors of response to trastuzumab and Lapatinib in breast cancer. Nat Rev Clin Oncol 2010;7:98–107. [7] Gomez HL, Doval DC, Chavez MA, Ang PC, Aziz Z, Nag S, et al. Efficacy and safety of Lapatinib as first-line therapy for ErbB2-amplified locally advanced or metastatic breast cancer. J Clin Oncol 2008;26:2999–3005. [8] Liu L, Greger J, Shi H, Liu Y, Greshock J, Annan R, et al. Novel mechanism of Lapatinib resistance in HER2-positive breast tumor cells: activation of AXL. Cancer Res 2009;69:6871–8. [9] Xia W, Bacus S, Husain I, Liu L, Zhao S, Liu Z, et al. Resistance to ErbB2 tyrosine kinase inhibitors in breast cancer is mediated by calcium-dependent activation of RelA. Mol Cancer Ther 2010;9:292–9. [10] Hynes NE, Dey JH. PI3K inhibition overcomes trastuzumab resistance. blockade of ErbB2/ErbB3 is not always enough. Cancer Cell 2009;15:353–5. [11] Berns K, Horlings HM, Hennessy BT, Madiredjo M, Hijmans EM, Beelen K, et al. A functional genetic approach identifies the PI3K pathway as a major determinant of trastuzumab resistance in breast cancer. Cancer Cell 2007;12:395–402. [12] Park BH, Davidson NE. PI3 kinase activation and response to trastuzumab therapy: what’s neu with herceptin resistance? Cancer Cell 2007;12:297–9.
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S. Chen et al. / Medical Hypotheses 77 (2011) 206–208
[13] Zoppoli G, Moran E, Soncini D, Cea M, Garuti A, Rocco I, et al. ras-Induced resistance to lapatinib is overcome by MEK inhibition. Curr Cancer Drug Targets 2010;10:168–75. [14] Martin AP, Mitchell C, Rahmani M, Nephew KP, Grant S, Dent P. Inhibition of MCL-1 enhances Lapatinib toxicity and overcomes Lapatinib resistance via BAK-dependent autophagy. Cancer Biol Ther 2009;8:2084–96. [15] Martin AP, Miller A, Emad L, Rahmani M, Walker T, Mitchell C, et al. Lapatinib resistance in HCT116 cells is mediated by elevated MCL-1 expression and decreased BAK activation and not by ERBB receptor kinase mutation. Mol Pharmacol 2008;74:807–22. [16] Levine B, Klionsky DJ. Development by self-digestion: molecular mechanisms and biological functions of autophagy. Dev Cell 2004;6:463–77. [17] Mathew R, Karantza-Wadsworth V, White E. Role of autophagy in cancer. Nat Rev Cancer 2007;7:961–7. [18] Xie Z, Klionsky DJ. Autophagosome formation: core machinery and adaptations. Nat Cell Biol 2007;9:1102–9. [19] Tanida I. Autophagosome formation and molecular mechanism of autophagy. Antioxid Redox Signal 2010 [Epub ahead of print]. [20] Hara T, Nakamura K, Matsui M, Yamamoto A, Nakahara Y, Suzuki-Migishima R, et al. Suppression of basal autophagy in neural cells causes neurodegenerative disease in mice. Nature 2006;441:885–9. [21] Komatsu M, Waguri S, Chiba T, Murata S, Iwata J, Tanida I, et al. Loss of autophagy in the central nervous system causes neurodegeneration in mice. Nature 2006;441:880–4. [22] Aguirre-Ghiso JA. The problem of cancer dormancy: understanding the basic mechanisms and identifying therapeutic opportunities. Cell Cycle 2006;5: 1740–3. [23] Degenhardt K, Mathew R, Beaudoin B, Bray K, Anderson D, Chen G, et al. Autophagy promotes tumor cell survival and restricts necrosis, inflammation, and tumorigenesis. Cancer Cell 2006;10:51–64. [24] Jin S, White E. Role of autophagy in cancer: management of metabolic stress. Autophagy 2007;3:28–31. [25] Karantza-Wadsworth V, Patel S, Kravchuk O, Chen G, Mathew R, Jin S, et al. Autophagy mitigates metabolic stress and genome damage in mammary tumorigenesis. Genes Dev 2007;21:1621–35.
[26] Liang XH, Jackson S, Seaman M, Brown K, Kempkes B, Hibshoosh H, et al. Induction of autophagy and inhibition of tumorigenesis by beclin 1. Nature 1999;402:672–6. [27] Qu X, Yu J, Bhagat G, Furuya N, Hibshoosh H, Troxel A, et al. Promotion of tumorigenesis by heterozygous disruption of the beclin 1 autophagy gene. J Clin Invest 2003;112:1809–20. [28] Marino G, Salvador-Montoliu N, Fueyo A, Knecht E, Mizushima N, Lopez-Otin C. Tissue-specific autophagy alterations and increased tumorigenesis in mice deficient in Atg4C/autophagin-3. J Biol Chem 2007;282:18573–83. [29] Karantza-Wadsworth V, White E. Role of autophagy in breast cancer. Autophagy 2007;3:610–3. [30] Chen S, Rehman SK, Zhang W, Wen A, Yao L, Zhang J. Autophagy is a therapeutic target in anticancer drug resistance. Biochim Biophys Acta 2010;1806:220–9. [31] Vazquez-Martin A, Oliveras-Ferraros C, Menendez JA. Autophagy facilitates the development of breast cancer resistance to the anti-HER2 monoclonal antibody trastuzumab. PLoS One 2009;4:e6251. [32] Bellodi C, Lidonnici MR, Hamilton A, Helgason GV, Soliera AR, Ronchetti M, et al. Targeting autophagy potentiates tyrosine kinase inhibitor-induced cell death in Philadelphia chromosome-positive cells, including primary CML stem cells. J Clin Invest 2009;119:1109–23. [33] Kawai A, Uchiyama H, Takano S, Nakamura N, Ohkuma S. Autophagosomelysosome fusion depends on the pH in acidic compartments in CHO cells. Autophagy 2007;3:154–7. [34] Kim PK, Hailey DW, Mullen RT, Lippincott-Schwartz J. Ubiquitin signals autophagic degradation of cytosolic proteins and peroxisomes. Proc Natl Acad Sci USA 2008;105:20567–74. [35] Rzymski T, Milani M, Singleton DC, Harris AL. Role of ATF4 in regulation of autophagy and resistance to drugs and hypoxia. Cell Cycle 2009;8: 3838–47. [36] Milani M, Rzymski T, Mellor HR, Pike L, Bottini A, Generali D, et al. The role of ATF4 stabilization and autophagy in resistance of breast cancer cells treated with Bortezomib. Cancer Res 2009;69:4415–23. [37] Martinet W, De Meyer GR, Andries L, Herman AG, Kockx MM. In situ detection of starvation-induced autophagy. J Histochem Cytochem 2006;54:85–96.
Contents lists available at ScienceDirect
Medical Hypotheses journal homepage: www.elsevier.com/locate/mehy
Autophagy facilitates the Lapatinib resistance of HER2 positive breast cancer cells Suning Chen a,1, Xiumin Li b,1, Juan Feng a, Ying Chang a, Zhirui Wang a, Aidong Wen a,⇑ a b
Department of Pharmacy, Xijing Hospital, The Fourth Military Medical University, ChangLe West Road #15, 710032 Xi’an, Shaanxi Province, People’s Republic of China Department of Pharmacy, General Hospital of Beijing Military Region, 100700 Beijing, People’s Republic of China
a r t i c l e
i n f o
Article history: Received 6 January 2011 Accepted 8 April 2011
a b s t r a c t ErbB2 receptor (HER2) tyrosine kinase was overexpressed in about 25% breast cancers, and was correlated with extremely aggressive phenotype and poor prognosis. Lapatinib, an oral, reversible inhibitor of both ErbB2 and EGFR tyrosine kinases, was approved in combination with capecitabine for treating advanced stage ErbB2 positive breast cancers. However, the clinical response of Lapatinib was seriously limited by the drug resistance. We established the Lapatinib resistant breast cancer cell lines and the preliminary data demonstrated the increased autophagosome formation in the stable resistant cells. The resistant cells were re-sensitized to Lapatinib after treated with autophagy inhibitor. According to our preliminary data and related reference, we hypothesized that autophagy could facilitate the ErbB2 positive breast cancer cells to be Lapatinib resistant and promoted the survival of the resistant cells. The abrogation of autophagy might restore the drug sensitivity. Autophagy might be one of the targets to overcome the Lapatinib resistance. Crown Copyright Ó 2011 Published by Elsevier Ltd. All rights reserved.
Introduction Overexpression of the ErbB2 receptor (HER2) tyrosine kinase can be found in about 25% breast cancers, and is associated with extremely aggressive cancer phenotype and worse prognosis [1– 3]. As an oral, reversible inhibitor of both ErbB2 and EGFR tyrosine kinases, Lapatinib (GW572016/Tykerb) was approved in combination with capecitabine for treating the advanced stage ErbB2 positive breast cancers that progressed on prior trastuzumab-based therapies by the FDA in 2007 [4,5]. However, the clinical response of Lapatinib was only about 24% [6,7]. Not all of the ErbB2 positive breast cancer cells responded to Lapatinib treatment, and resistance to Lapatinib developed in some patients and/or tumors during chronic exposure to the drug [8,9]. Since the therapy efficacy of Lapatinib was subjected to the intrinsic and acquired resistance, it is urgent to uncover the potential mechanisms conferring resistance to Lapatinib. Although previous research has provided evidence for possible mechanisms, to date, the reason to induce resistance to Lapatinib is not fully elucidated. For the resistance of trastuzumab, PTEN loss and PIK3CA mutations played an important role. Due to the fact that both Lapatinib and trastuzumab was based on the blocking of ErbB2-PI3K signal pathway [10–12], we cannot eliminate the involvement of PTEN loss and PIK3CA mutation in Lapatinib resistance. Other evidence also showed that increased expression of the membrane receptor tyrosine kinase AXL conferred the resistance to ⇑ Corresponding author. Tel.: +86 29 84773636. 1
E-mail address: [email protected] (A. Wen). These authors contributed equally to this work.
Lapatinib and trastuzumab. The combination with AXL inhibitor could particularly reverse the resistance to Lapatinib [8]. Also, Ras could induce the resistance to Lapatinib and overcame by MEK inhibition [13]. Remarkably, MCL-1, one member of Bcl-2 family, induced the Lapatinib resistance in HCT116 cells and the inhibition of MCL-1 could restore the sensitivity of Lapatinib toxicity via BAK-dependent autophagy [14,15]. However, other mechanisms which induce Lapatinib resistance are not well characterized yet. Autophagy is a cellular catabolic degradation response to stress or metabolic starvation whereby cellular proteins are engulfed, digested and recycled to sustain cellular metabolism [16,17]. The expanding membrane enwraps portions of the cytoplasm and leads to the formation of double-membrane-bound, sequestering vesicles, called autophagosomes, which is the unique character of autophagy. Autophagosomes subsequently fuse with lysosomes and the inner membrane of the autophagosome together with the enclosed cargo is degraded. The resulting macromolecules are released into the cytosol through lysosomal membrane permeases for recycling [18]. There are at least 30 ATG genes involved in autophagosome formation, including Atg1, Atg8 and Atg23 etc. [19]. The basal level of autophagy has an important homeostatic function to maintain the protein and organelle quality control and prevent the accumulation of defective organelles and aggregated proteins [20,21]. However, the role of autophagy in cancer remains controversial [22–25]. Since the loss of the essential autophagy gene such as Becn1 and Atg4C is found frequently in human breast and prostate cancers, it was believed that autophagy had an important role in tumor suppression [26–28]. Paradoxically,
0306-9877/$ - see front matter Crown Copyright Ó 2011 Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.mehy.2011.04.013
S. Chen et al. / Medical Hypotheses 77 (2011) 206–208
more and more data demonstrated that autophagy could protect cancer cells against the metabolic stress including drug resistance [25,29,30]. For example, induced autophagy could facilitate the HER2 positive breast cancer cells to be resistant to herceptin [30,31]. Furthermore, targeting autophagy potentiates tyrosine kinase inhibitor induced cell death in CML stem cells [32]. We established the stable resistant cells to Lapatinib in BT474 HER2 positive breast cancer cell lines. Notably, the autophagosome formation increased a lot in the Lapatinib resistant cells. Combined the literature and our preliminary data, we believed that autophagy might be regarded as an important survival mechanism of the breast cancer cells resistant to Lapatinib. Hypothesis We hypothesized that most of the sensitive cells will be killed during the long-term treatment of Lapatinib to HER2 positive breast cancer cells. But a few cells remain the tolerance to Lapatinib due to the cell’s protective mechanism of autophagy induced by the metabolic stress environment (Fig. 1). So, autophagy can facilitate the acquired Lapatinib resistance of HER2 positive breast cancer cells, which might be one of reasons of tumor recurrence and metastasis. Due to the protection of autophagy from Lapatinib toxicity, the inhibition of the autophagy might restore the drug sensitivity. The autophagy inhibitors such as hydroxychloroquine (HCQ), 3-methyladenine (3-MA) might be helpful to restore the sensitivity of the resistant cells to Lapatinib via abolishing the formation process and degradation ability of autophagosome [33,34]. Alternatively, the abrogation of key molecules to form autophagosome, such as Atg1, Atg8 etc., also might be useful to re-sensitize the Lapatinib treatment. It is promising to expect the autophagy inhibitors to be the next generation drugs to overcome the Lapatinib resistance of HER2 positive breast cancer cells. Hypothesis evaluation and discussion One of the most daunting clinical problems is the frequent relapse of tumors after treatment, mainly due to the drug resistance. Although autophagy was widely reported to be involved in drug resistance [31,35,36], it is not clear whether and how autophagy conferring Lapatinib resistance. Herein, according our hypothesis, there are several key points needed to pay close attention in the following experiment.
Fig. 1. Autophagy facilitates the Lapatinib resistance of HER2 positive breast cancer cells.
207
We detected the increasing autophagosomes formation in the Lapatinib resistant breast cancer cells with transmission electron microscopy, which was currently the golden standard to monitor autophagy in situ [37]. To further validate this hypothesis, we should firstly confirm the activation of autophagic molecules in Lapatinib resistant cells compared with the parental, such as Beclin1, ATG7, LC3-II etc. Secondly, it is critical to identify the function of autophagy in Lapatinib resistant cells through blocking autophagy with the specific inhibitor to abolish the autophagosome formation, such as chloroquine (CQ) and bafilomycin A1 (BA) [31,32]. Also we can use the specific shRNA targeting the key autophagy associated molecules, such as ATG5 and ATG7. If autophagy sustains the cell viability in resistant cells, the block of autophagy will induce the resistant cells much more susceptible to Lapatinib toxicity. However, whether autophagy is a death-induced mechanism or a protective effort for cellular survival is still a controversy. So the autophagy inhibitor might increase the tumor incidence under some circumstance. Undoubtedly, we should pay more attention to the autophagy inhibitor treatment. Finally, it is also very important to clarify the mechanism to induce the autophagy in Lapatinib resistant breast cancer cells. So far, there are several key mechanisms to explain the autophagy generation, such as PI3K-Akt-mTOR, LKB1-AMPK-mTOR, P53 and Beclin1 etc. We need to focus one or more pathway to elucidate the reason of autophagy formation in Lapatinib resistant cells. Since drug resistance is the main challenge for the therapeutic efficacy of Lapatinib, it is very important to explore the possible resistant mechanism. We believe that it will be much more helpful to elucidate the function of autophagy in Lapatinib resistance, and also will provide the potential targets to overcome Lapatinib resistance. Conflicts of interest None declared. References [1] Curigliano G, Viale G, Bagnardi V, Fumagalli L, Locatelli M, Rotmensz N, et al. Clinical relevance of HER2 overexpression/amplification in patients with small tumor size and node-negative breast cancer. J Clin Oncol 2009;27:5693–9. [2] Pommier SJ, Quan GG, Christante D, Muller P, Newell AE, Olson SB, et al. Characterizing the HER2/neu status and metastatic potential of breast cancer stem/progenitor cells. Ann Surg Oncol 2010;17:613–23. [3] Jemal A, Siegel R, Xu J, Ward E. Cancer statistics, 2010. CA Cancer J Clin 2010;60:277–300. [4] Geyer CE, Forster J, Lindquist D, Chan S, Romieu CG, Pienkowski T, et al. Lapatinib plus capecitabine for HER2-positive advanced breast cancer. N Engl J Med 2006;355:2733–43. [5] Macfarlane RJ, Gelmon KA. Lapatinib for breast cancer: a review of the current literature. Expert Opin Drug Saf 2011;10:109–21. [6] Esteva FJ, Yu D, Hung MC, Hortobagyi GN. Molecular predictors of response to trastuzumab and Lapatinib in breast cancer. Nat Rev Clin Oncol 2010;7:98–107. [7] Gomez HL, Doval DC, Chavez MA, Ang PC, Aziz Z, Nag S, et al. Efficacy and safety of Lapatinib as first-line therapy for ErbB2-amplified locally advanced or metastatic breast cancer. J Clin Oncol 2008;26:2999–3005. [8] Liu L, Greger J, Shi H, Liu Y, Greshock J, Annan R, et al. Novel mechanism of Lapatinib resistance in HER2-positive breast tumor cells: activation of AXL. Cancer Res 2009;69:6871–8. [9] Xia W, Bacus S, Husain I, Liu L, Zhao S, Liu Z, et al. Resistance to ErbB2 tyrosine kinase inhibitors in breast cancer is mediated by calcium-dependent activation of RelA. Mol Cancer Ther 2010;9:292–9. [10] Hynes NE, Dey JH. PI3K inhibition overcomes trastuzumab resistance. blockade of ErbB2/ErbB3 is not always enough. Cancer Cell 2009;15:353–5. [11] Berns K, Horlings HM, Hennessy BT, Madiredjo M, Hijmans EM, Beelen K, et al. A functional genetic approach identifies the PI3K pathway as a major determinant of trastuzumab resistance in breast cancer. Cancer Cell 2007;12:395–402. [12] Park BH, Davidson NE. PI3 kinase activation and response to trastuzumab therapy: what’s neu with herceptin resistance? Cancer Cell 2007;12:297–9.
208
S. Chen et al. / Medical Hypotheses 77 (2011) 206–208
[13] Zoppoli G, Moran E, Soncini D, Cea M, Garuti A, Rocco I, et al. ras-Induced resistance to lapatinib is overcome by MEK inhibition. Curr Cancer Drug Targets 2010;10:168–75. [14] Martin AP, Mitchell C, Rahmani M, Nephew KP, Grant S, Dent P. Inhibition of MCL-1 enhances Lapatinib toxicity and overcomes Lapatinib resistance via BAK-dependent autophagy. Cancer Biol Ther 2009;8:2084–96. [15] Martin AP, Miller A, Emad L, Rahmani M, Walker T, Mitchell C, et al. Lapatinib resistance in HCT116 cells is mediated by elevated MCL-1 expression and decreased BAK activation and not by ERBB receptor kinase mutation. Mol Pharmacol 2008;74:807–22. [16] Levine B, Klionsky DJ. Development by self-digestion: molecular mechanisms and biological functions of autophagy. Dev Cell 2004;6:463–77. [17] Mathew R, Karantza-Wadsworth V, White E. Role of autophagy in cancer. Nat Rev Cancer 2007;7:961–7. [18] Xie Z, Klionsky DJ. Autophagosome formation: core machinery and adaptations. Nat Cell Biol 2007;9:1102–9. [19] Tanida I. Autophagosome formation and molecular mechanism of autophagy. Antioxid Redox Signal 2010 [Epub ahead of print]. [20] Hara T, Nakamura K, Matsui M, Yamamoto A, Nakahara Y, Suzuki-Migishima R, et al. Suppression of basal autophagy in neural cells causes neurodegenerative disease in mice. Nature 2006;441:885–9. [21] Komatsu M, Waguri S, Chiba T, Murata S, Iwata J, Tanida I, et al. Loss of autophagy in the central nervous system causes neurodegeneration in mice. Nature 2006;441:880–4. [22] Aguirre-Ghiso JA. The problem of cancer dormancy: understanding the basic mechanisms and identifying therapeutic opportunities. Cell Cycle 2006;5: 1740–3. [23] Degenhardt K, Mathew R, Beaudoin B, Bray K, Anderson D, Chen G, et al. Autophagy promotes tumor cell survival and restricts necrosis, inflammation, and tumorigenesis. Cancer Cell 2006;10:51–64. [24] Jin S, White E. Role of autophagy in cancer: management of metabolic stress. Autophagy 2007;3:28–31. [25] Karantza-Wadsworth V, Patel S, Kravchuk O, Chen G, Mathew R, Jin S, et al. Autophagy mitigates metabolic stress and genome damage in mammary tumorigenesis. Genes Dev 2007;21:1621–35.
[26] Liang XH, Jackson S, Seaman M, Brown K, Kempkes B, Hibshoosh H, et al. Induction of autophagy and inhibition of tumorigenesis by beclin 1. Nature 1999;402:672–6. [27] Qu X, Yu J, Bhagat G, Furuya N, Hibshoosh H, Troxel A, et al. Promotion of tumorigenesis by heterozygous disruption of the beclin 1 autophagy gene. J Clin Invest 2003;112:1809–20. [28] Marino G, Salvador-Montoliu N, Fueyo A, Knecht E, Mizushima N, Lopez-Otin C. Tissue-specific autophagy alterations and increased tumorigenesis in mice deficient in Atg4C/autophagin-3. J Biol Chem 2007;282:18573–83. [29] Karantza-Wadsworth V, White E. Role of autophagy in breast cancer. Autophagy 2007;3:610–3. [30] Chen S, Rehman SK, Zhang W, Wen A, Yao L, Zhang J. Autophagy is a therapeutic target in anticancer drug resistance. Biochim Biophys Acta 2010;1806:220–9. [31] Vazquez-Martin A, Oliveras-Ferraros C, Menendez JA. Autophagy facilitates the development of breast cancer resistance to the anti-HER2 monoclonal antibody trastuzumab. PLoS One 2009;4:e6251. [32] Bellodi C, Lidonnici MR, Hamilton A, Helgason GV, Soliera AR, Ronchetti M, et al. Targeting autophagy potentiates tyrosine kinase inhibitor-induced cell death in Philadelphia chromosome-positive cells, including primary CML stem cells. J Clin Invest 2009;119:1109–23. [33] Kawai A, Uchiyama H, Takano S, Nakamura N, Ohkuma S. Autophagosomelysosome fusion depends on the pH in acidic compartments in CHO cells. Autophagy 2007;3:154–7. [34] Kim PK, Hailey DW, Mullen RT, Lippincott-Schwartz J. Ubiquitin signals autophagic degradation of cytosolic proteins and peroxisomes. Proc Natl Acad Sci USA 2008;105:20567–74. [35] Rzymski T, Milani M, Singleton DC, Harris AL. Role of ATF4 in regulation of autophagy and resistance to drugs and hypoxia. Cell Cycle 2009;8: 3838–47. [36] Milani M, Rzymski T, Mellor HR, Pike L, Bottini A, Generali D, et al. The role of ATF4 stabilization and autophagy in resistance of breast cancer cells treated with Bortezomib. Cancer Res 2009;69:4415–23. [37] Martinet W, De Meyer GR, Andries L, Herman AG, Kockx MM. In situ detection of starvation-induced autophagy. J Histochem Cytochem 2006;54:85–96.