Breast Cancer — Loss of PTEN Predicts Resistance to Treatment
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《新英格兰医药杂志》
PTEN, the lipid phosphatase and tensin homologue, is a key tumor suppressor. Mutations resulting in the loss of PTEN or the loss of its function are common and functionally relevant in tumors of different histologic origins, including breast cancer.1 A recent study by Nagata and colleagues2 shows that PTEN not only antagonizes tumorigenesis but also sensitizes breast cancers to targeted therapy with trastuzumab (Herceptin), a humanized monoclonal antibody against ErbB2 (also referred to as HER2/neu), a membrane-receptor tyrosine kinase in the epidermal growth factor receptor family.3
PTEN normally opposes the activation of the proto-oncogenic phosphatidylinositol 3' kinase (PI3K)–Akt signaling pathway (Figure 1A).1 Approximately 50 percent of patients with breast cancer have a mutation in or loss of at least one copy of the PTEN gene, which results in the activation of PI3K signaling. The severity of PTEN mutations strongly correlates with the tumor stage and grade. For example, complete loss of PTEN is more frequent in metastatic cancer than in primary tumors.1 The loss of one copy of PTEN increases the risk that a tumor will develop, and the level of expression of PTEN dramatically affects the initiation and progression of tumors.4 The study by Nagata and colleagues suggests that the gene dose and, therefore, the levels of expression of PTEN may also determine the response to therapy.
Figure 1. Resistance to Trastuzumab Due to PTEN Deficiency.
In Panel A, the overexpression of ErbB2 leads to its activation through autophosphorylation (P). As a result, Src kinase and phosphatidylinositol 3' kinase (PI3K), with its regulatory subunits p85 and p110, are recruited to the receptor and kept in their active state. The activation of PI3K leads in turn to the activation of the proto-oncogenic signaling pathway consisting of Akt and the mammalian target of rapamycin (mTOR). Nagata and colleagues2 show that when active, Src can inactivate PTEN through the phosphorylation of its C-terminal end. This triggers the production of elevated levels of phosphatidylinositol 3,4,5-triphosphate (PIP3), further potentiating the activation of PI3K. On binding to the ErbB2 receptor, trastuzumab causes the dissociation of the receptor from Src and its inactivation through unknown mechanisms (Panel B). PTEN thus becomes free to antagonize the activation of the PI3K–AKT–mTOR signaling pathway through the dephosphorylation of PIP3. Trastuzumab could be combined with drugs such as sirolimus (rapamycin) and its analogues, everolimus (RAD001) and CCI-779, which inhibit mTOR, to block this critical signaling pathway at two different points. Nagata et al. show that a partial or total deficiency of PTEN (Panel C) may account for resistance to trastuzumab.2
Up to 30 percent of human breast cancers overexpress ErbB2, as do other types of cancer, and such overexpression correlates with extremely aggressive cancers and a poor prognosis.3 In addition, intragenic ErbB2 mutations in the kinase domain of the receptor have recently been identified in lung tumors.5 Trastuzumab binds specifically to the extracellular domain of ErbB2 (Figure 1) and can induce down-regulation and inactivation of the receptor through several mechanisms.3 Inactivation, in turn, results in poorly understood antitumoral responses, including arrest of the cell cycle. Although trastuzumab prolongs survival among patients with cancer when administered with chemotherapy, it does not cure cancer. Furthermore, many patients have primary resistance to trastuzumab for unknown reasons.3
Nagata and colleagues provide data that clarify the antitumoral mechanism of trastuzumab and help clarify the mechanism underlying resistance. They show that, on binding to the ErbB2 receptor, trastuzumab stabilizes and activates the PTEN tumor suppressor and consequently down-regulates the PI3K–Akt signaling pathway (Figure 1A).2 When the expression of PTEN is reduced or abrogated, this chain of events is interrupted and the antitumoral effects of trastuzumab are impaired (Figure 1B). The authors therefore predicted that the presence of low levels of PTEN would correlate with unresponsiveness to trastuzumab treatment and subsequently confirmed this correlation in a small group of patients.2 Prospective studies using larger cohorts of patients and thorough in vivo genetic analyses of mice with various degrees of Pten function are warranted.
Because the level of expression of PTEN is critical to tumorigenesis and apparently modulates the response to therapy, the systematic analysis of the activation status and level of expression of PTEN and PI3K in tumors is now imperative. So, too, are experiments to determine whether gain-of-function mutations in the ErbB2 and PI3K genes also correlate with unresponsiveness to trastuzumab and other small-molecule inhibitors of ErbB2. The new findings call for a renewed focus on PTEN as a possible target for therapeutic intervention in tumors that lack one copy of PTEN. Drugs that augment PTEN levels may sensitize these tumors to trastuzumab and other drugs. One could also envision the therapeutic use of a combination of trastuzumab and PI3K inhibitors (when these become available) or downstream inhibitors of the PI3K–Akt signaling pathway, such as sirolimus (rapamycin) and its analogues.
Source Information
From the Cancer Biology and Genetics Program, Memorial-Sloan Kettering Cancer Center, New York.
References
Di Cristofano A, Pandolfi PP. The multiple roles of PTEN in tumor suppression. Cell 2000;100:387-390.
Nagata Y, Lan K-H, Zhou X, et al. PTEN activation contributes to tumor inhibition by trastuzumab, and loss of PTEN predicts trastuzumab resistance in patients. Cancer Cell 2004;6:117-127.
Yu D, Hung MC. Overexpression of ErbB2 in cancer and ErbB2-targeting strategies. Oncogene 2000;19:6115-6121.
Trotman LC, Niki M, Dotan Z, et al. Pten dose dictates cancer progression. PLoS Biol 2003;1(3):E59.
Stephens P, Hunter C, Bignell G, et al. Intragenic ERBB2 kinase mutations in tumors. Nature 2004;431:525-526.(Pier Paolo Pandolfi, M.D.)
PTEN normally opposes the activation of the proto-oncogenic phosphatidylinositol 3' kinase (PI3K)–Akt signaling pathway (Figure 1A).1 Approximately 50 percent of patients with breast cancer have a mutation in or loss of at least one copy of the PTEN gene, which results in the activation of PI3K signaling. The severity of PTEN mutations strongly correlates with the tumor stage and grade. For example, complete loss of PTEN is more frequent in metastatic cancer than in primary tumors.1 The loss of one copy of PTEN increases the risk that a tumor will develop, and the level of expression of PTEN dramatically affects the initiation and progression of tumors.4 The study by Nagata and colleagues suggests that the gene dose and, therefore, the levels of expression of PTEN may also determine the response to therapy.
Figure 1. Resistance to Trastuzumab Due to PTEN Deficiency.
In Panel A, the overexpression of ErbB2 leads to its activation through autophosphorylation (P). As a result, Src kinase and phosphatidylinositol 3' kinase (PI3K), with its regulatory subunits p85 and p110, are recruited to the receptor and kept in their active state. The activation of PI3K leads in turn to the activation of the proto-oncogenic signaling pathway consisting of Akt and the mammalian target of rapamycin (mTOR). Nagata and colleagues2 show that when active, Src can inactivate PTEN through the phosphorylation of its C-terminal end. This triggers the production of elevated levels of phosphatidylinositol 3,4,5-triphosphate (PIP3), further potentiating the activation of PI3K. On binding to the ErbB2 receptor, trastuzumab causes the dissociation of the receptor from Src and its inactivation through unknown mechanisms (Panel B). PTEN thus becomes free to antagonize the activation of the PI3K–AKT–mTOR signaling pathway through the dephosphorylation of PIP3. Trastuzumab could be combined with drugs such as sirolimus (rapamycin) and its analogues, everolimus (RAD001) and CCI-779, which inhibit mTOR, to block this critical signaling pathway at two different points. Nagata et al. show that a partial or total deficiency of PTEN (Panel C) may account for resistance to trastuzumab.2
Up to 30 percent of human breast cancers overexpress ErbB2, as do other types of cancer, and such overexpression correlates with extremely aggressive cancers and a poor prognosis.3 In addition, intragenic ErbB2 mutations in the kinase domain of the receptor have recently been identified in lung tumors.5 Trastuzumab binds specifically to the extracellular domain of ErbB2 (Figure 1) and can induce down-regulation and inactivation of the receptor through several mechanisms.3 Inactivation, in turn, results in poorly understood antitumoral responses, including arrest of the cell cycle. Although trastuzumab prolongs survival among patients with cancer when administered with chemotherapy, it does not cure cancer. Furthermore, many patients have primary resistance to trastuzumab for unknown reasons.3
Nagata and colleagues provide data that clarify the antitumoral mechanism of trastuzumab and help clarify the mechanism underlying resistance. They show that, on binding to the ErbB2 receptor, trastuzumab stabilizes and activates the PTEN tumor suppressor and consequently down-regulates the PI3K–Akt signaling pathway (Figure 1A).2 When the expression of PTEN is reduced or abrogated, this chain of events is interrupted and the antitumoral effects of trastuzumab are impaired (Figure 1B). The authors therefore predicted that the presence of low levels of PTEN would correlate with unresponsiveness to trastuzumab treatment and subsequently confirmed this correlation in a small group of patients.2 Prospective studies using larger cohorts of patients and thorough in vivo genetic analyses of mice with various degrees of Pten function are warranted.
Because the level of expression of PTEN is critical to tumorigenesis and apparently modulates the response to therapy, the systematic analysis of the activation status and level of expression of PTEN and PI3K in tumors is now imperative. So, too, are experiments to determine whether gain-of-function mutations in the ErbB2 and PI3K genes also correlate with unresponsiveness to trastuzumab and other small-molecule inhibitors of ErbB2. The new findings call for a renewed focus on PTEN as a possible target for therapeutic intervention in tumors that lack one copy of PTEN. Drugs that augment PTEN levels may sensitize these tumors to trastuzumab and other drugs. One could also envision the therapeutic use of a combination of trastuzumab and PI3K inhibitors (when these become available) or downstream inhibitors of the PI3K–Akt signaling pathway, such as sirolimus (rapamycin) and its analogues.
Source Information
From the Cancer Biology and Genetics Program, Memorial-Sloan Kettering Cancer Center, New York.
References
Di Cristofano A, Pandolfi PP. The multiple roles of PTEN in tumor suppression. Cell 2000;100:387-390.
Nagata Y, Lan K-H, Zhou X, et al. PTEN activation contributes to tumor inhibition by trastuzumab, and loss of PTEN predicts trastuzumab resistance in patients. Cancer Cell 2004;6:117-127.
Yu D, Hung MC. Overexpression of ErbB2 in cancer and ErbB2-targeting strategies. Oncogene 2000;19:6115-6121.
Trotman LC, Niki M, Dotan Z, et al. Pten dose dictates cancer progression. PLoS Biol 2003;1(3):E59.
Stephens P, Hunter C, Bignell G, et al. Intragenic ERBB2 kinase mutations in tumors. Nature 2004;431:525-526.(Pier Paolo Pandolfi, M.D.)