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Understanding and Targeting MET Signaling in Solid Tumors - Are We There Yet?

Ariyawutyakorn W, Saichaemchan S, Varella-Garcia M - J Cancer (2016)

Bottom Line: Different technologies have been used to investigate the genomic and proteomic status of MET in cancer patients and its association with disease prognosis.We review the molecular mechanisms involved in the deregulation of the MET signaling pathway in solid tumors, the different technologies used for diagnosis, and the main factors that affect the outcome, emphasizing the urge for completing analytical and clinical validation of these tests.We also review the current clinical studies with MET targeted agents, which mostly focus on lung cancer.

View Article: PubMed Central - PubMed

Affiliation: 1. Faculty of Medicine, Chiang Mai University, 110 Intavarorod Rd., Muang, Chiang Mai, Thailand 50200.; 3. Department of Medicine, University of Colorado, Anschutz Medical Campus, 12801 East 17th Ave, RC1 South, L18-8118, Mail Stop 8117, Aurora, Colorado, USA 80045.

ABSTRACT
The MET signaling pathway plays an important role in normal physiology and its deregulation has proved critical for development of numerous solid tumors. Different technologies have been used to investigate the genomic and proteomic status of MET in cancer patients and its association with disease prognosis. Moreover, with the development of targeted therapeutic drugs, there is an urgent need to identify potential biomarkers for selection of patients who are more likely to derive benefit from these agents. Unfortunately, the variety of technical platforms and analysis criteria for diagnosis has brought confusion to the field and a lack of agreement in the evaluation of MET status as a prognostic or predictive marker for targeted therapy agents. We review the molecular mechanisms involved in the deregulation of the MET signaling pathway in solid tumors, the different technologies used for diagnosis, and the main factors that affect the outcome, emphasizing the urge for completing analytical and clinical validation of these tests. We also review the current clinical studies with MET targeted agents, which mostly focus on lung cancer.

No MeSH data available.


Related in: MedlinePlus

MET signaling pathway. After MET activation, PI3K can bind either to MET directly or indirectly with GAB1 and signals through the AKT/protein kinase B axis. AKT can inactivate the pro-apoptotic protein BCL-2 antagonist of cell death (BAD) and activate the E3 ubiquitin-protein ligase MDM2, which results in apoptosis suppression and cell survival promotion. Moreover, AKT can also activate mammalian target of rapamycin (mTOR), which stimulates protein synthesis and cell growth. MET activation also signals through the RAS-MAPK pathway. The nucleotide exchanger protein Son of Sevenless (SOS) activates RAS by binding with SHC and GRB2 (GRB2-SOS complex). This leads to activation of the v-raf murine sarcoma viral oncogene homolog B1 (RAF) kinases, which subsequently stimulates the MAPK effector kinase (MEK) and results in MAPK activation. MAPK phosphorylates ERK, which is the final effector of the cascade. The RAS-MAPK pathway is responsible for cell proliferation, cell motility and cell cycle progression. A third major downstream axis of MET signaling is the Signal transducer and activator of transcription 3 (STAT3) pathway. STAT3 can bind to MET directly resulting in STAT3 phosphorylation, which regulates cell transformation, tubulogenesis and invasion. Finally, the fourth major cascade of MET activation is through the IκBα-NF-κB complex. NF-κB is bound to IκBα forming an inactive form. The phosphorylation of either PI3K-AKT or SRC activates IκB kinase (IKK) and results in degradation of IκBs. NF-κB is then released and translocated to the nucleus to stimulate gene transcription.
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Figure 2: MET signaling pathway. After MET activation, PI3K can bind either to MET directly or indirectly with GAB1 and signals through the AKT/protein kinase B axis. AKT can inactivate the pro-apoptotic protein BCL-2 antagonist of cell death (BAD) and activate the E3 ubiquitin-protein ligase MDM2, which results in apoptosis suppression and cell survival promotion. Moreover, AKT can also activate mammalian target of rapamycin (mTOR), which stimulates protein synthesis and cell growth. MET activation also signals through the RAS-MAPK pathway. The nucleotide exchanger protein Son of Sevenless (SOS) activates RAS by binding with SHC and GRB2 (GRB2-SOS complex). This leads to activation of the v-raf murine sarcoma viral oncogene homolog B1 (RAF) kinases, which subsequently stimulates the MAPK effector kinase (MEK) and results in MAPK activation. MAPK phosphorylates ERK, which is the final effector of the cascade. The RAS-MAPK pathway is responsible for cell proliferation, cell motility and cell cycle progression. A third major downstream axis of MET signaling is the Signal transducer and activator of transcription 3 (STAT3) pathway. STAT3 can bind to MET directly resulting in STAT3 phosphorylation, which regulates cell transformation, tubulogenesis and invasion. Finally, the fourth major cascade of MET activation is through the IκBα-NF-κB complex. NF-κB is bound to IκBα forming an inactive form. The phosphorylation of either PI3K-AKT or SRC activates IκB kinase (IKK) and results in degradation of IκBs. NF-κB is then released and translocated to the nucleus to stimulate gene transcription.

Mentions: Following the HGF binding, the kinase activity of MET is switched on by receptor dimerization and trans-phosphorylation of two catalytic tyrosine residues (Tyr1234 and Tyr1235) within the kinase activation loop, then by phosphorylation of two additional docking tyrosine kinases in the C-terminal tail (Tyr1349 and Tyr1356). These tyrosines recruit signaling effectors including the adaptor proteins growth factor receptor-bound protein (GRB2), Src homology-2-containing (SHC), v-crk sarcoma virus CT10 oncogene homolog (CRK), and CRK-like (CRKL) 6,14. Moreover, the adaptor protein GRB2-association binding protein 1 (GAB1) can bind either to MET directly or indirectly through GRB2 6. Phosphorylation of these different effectors initiate important downstream signaling pathways for cell proliferation, morphogenesis, survival, migration and angiogenesis, such as the cascades related to PI3K-Akt, RAS-MAP kinase, STAT3 and nuclear factor-κB (NF-κB) complex 6,14,15. These pathways are summarized in Figure 2. After MET activation, PI3K can bind either to MET directly or indirectly with GAB1 and signals through the AKT/protein kinase B axis. AKT can inactivate the pro-apoptotic protein BCL-2 antagonist of cell death (BAD) and activate the E3 ubiquitin-protein ligase MDM2, which results in apoptosis suppression and cell survival promotion 16. Moreover, AKT can also activate mammalian target of rapamycin (mTOR), which stimulates protein synthesis and cell growth. MET activation also signals through the RAS-MAPK pathway. The nucleotide exchanger protein Son of Sevenless (SOS) activates RAS by binding with SHC and GRB2 (GRB2-SOS complex). This leads to activation of the v-raf murine sarcoma viral oncogene homolog B1 (RAF) kinases, which subsequently stimulates the MAPK effector kinase (MEK) and results in MAPK activation. MAPK phosphorylates,the final effector of the cascade, ERK. The RAS-MAPK pathway is responsible for cell proliferation, cell motility and cell cycle progression 17. A third major downstream axis of MET signaling is the Signal transducer and activator of transcription 3 (STAT3) pathway. STAT3 can bind to MET directly resulting in STAT3 phosphorylation, which regulates cell transformation, tubulogenesis and invasion 10. Finally, the fourth major cascade of MET activation is through the IκBα-NF-κB complex. NF-κB is bound to IκBα forming an inactive form. The phosphorylation of either PI3K-AKT or SRC activates IκB kinase (IKK) and results in degradation of IκBs. NF-κB is then released and translocated to the nucleus to stimulate gene transcription 15.


Understanding and Targeting MET Signaling in Solid Tumors - Are We There Yet?

Ariyawutyakorn W, Saichaemchan S, Varella-Garcia M - J Cancer (2016)

MET signaling pathway. After MET activation, PI3K can bind either to MET directly or indirectly with GAB1 and signals through the AKT/protein kinase B axis. AKT can inactivate the pro-apoptotic protein BCL-2 antagonist of cell death (BAD) and activate the E3 ubiquitin-protein ligase MDM2, which results in apoptosis suppression and cell survival promotion. Moreover, AKT can also activate mammalian target of rapamycin (mTOR), which stimulates protein synthesis and cell growth. MET activation also signals through the RAS-MAPK pathway. The nucleotide exchanger protein Son of Sevenless (SOS) activates RAS by binding with SHC and GRB2 (GRB2-SOS complex). This leads to activation of the v-raf murine sarcoma viral oncogene homolog B1 (RAF) kinases, which subsequently stimulates the MAPK effector kinase (MEK) and results in MAPK activation. MAPK phosphorylates ERK, which is the final effector of the cascade. The RAS-MAPK pathway is responsible for cell proliferation, cell motility and cell cycle progression. A third major downstream axis of MET signaling is the Signal transducer and activator of transcription 3 (STAT3) pathway. STAT3 can bind to MET directly resulting in STAT3 phosphorylation, which regulates cell transformation, tubulogenesis and invasion. Finally, the fourth major cascade of MET activation is through the IκBα-NF-κB complex. NF-κB is bound to IκBα forming an inactive form. The phosphorylation of either PI3K-AKT or SRC activates IκB kinase (IKK) and results in degradation of IκBs. NF-κB is then released and translocated to the nucleus to stimulate gene transcription.
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Related In: Results  -  Collection

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Figure 2: MET signaling pathway. After MET activation, PI3K can bind either to MET directly or indirectly with GAB1 and signals through the AKT/protein kinase B axis. AKT can inactivate the pro-apoptotic protein BCL-2 antagonist of cell death (BAD) and activate the E3 ubiquitin-protein ligase MDM2, which results in apoptosis suppression and cell survival promotion. Moreover, AKT can also activate mammalian target of rapamycin (mTOR), which stimulates protein synthesis and cell growth. MET activation also signals through the RAS-MAPK pathway. The nucleotide exchanger protein Son of Sevenless (SOS) activates RAS by binding with SHC and GRB2 (GRB2-SOS complex). This leads to activation of the v-raf murine sarcoma viral oncogene homolog B1 (RAF) kinases, which subsequently stimulates the MAPK effector kinase (MEK) and results in MAPK activation. MAPK phosphorylates ERK, which is the final effector of the cascade. The RAS-MAPK pathway is responsible for cell proliferation, cell motility and cell cycle progression. A third major downstream axis of MET signaling is the Signal transducer and activator of transcription 3 (STAT3) pathway. STAT3 can bind to MET directly resulting in STAT3 phosphorylation, which regulates cell transformation, tubulogenesis and invasion. Finally, the fourth major cascade of MET activation is through the IκBα-NF-κB complex. NF-κB is bound to IκBα forming an inactive form. The phosphorylation of either PI3K-AKT or SRC activates IκB kinase (IKK) and results in degradation of IκBs. NF-κB is then released and translocated to the nucleus to stimulate gene transcription.
Mentions: Following the HGF binding, the kinase activity of MET is switched on by receptor dimerization and trans-phosphorylation of two catalytic tyrosine residues (Tyr1234 and Tyr1235) within the kinase activation loop, then by phosphorylation of two additional docking tyrosine kinases in the C-terminal tail (Tyr1349 and Tyr1356). These tyrosines recruit signaling effectors including the adaptor proteins growth factor receptor-bound protein (GRB2), Src homology-2-containing (SHC), v-crk sarcoma virus CT10 oncogene homolog (CRK), and CRK-like (CRKL) 6,14. Moreover, the adaptor protein GRB2-association binding protein 1 (GAB1) can bind either to MET directly or indirectly through GRB2 6. Phosphorylation of these different effectors initiate important downstream signaling pathways for cell proliferation, morphogenesis, survival, migration and angiogenesis, such as the cascades related to PI3K-Akt, RAS-MAP kinase, STAT3 and nuclear factor-κB (NF-κB) complex 6,14,15. These pathways are summarized in Figure 2. After MET activation, PI3K can bind either to MET directly or indirectly with GAB1 and signals through the AKT/protein kinase B axis. AKT can inactivate the pro-apoptotic protein BCL-2 antagonist of cell death (BAD) and activate the E3 ubiquitin-protein ligase MDM2, which results in apoptosis suppression and cell survival promotion 16. Moreover, AKT can also activate mammalian target of rapamycin (mTOR), which stimulates protein synthesis and cell growth. MET activation also signals through the RAS-MAPK pathway. The nucleotide exchanger protein Son of Sevenless (SOS) activates RAS by binding with SHC and GRB2 (GRB2-SOS complex). This leads to activation of the v-raf murine sarcoma viral oncogene homolog B1 (RAF) kinases, which subsequently stimulates the MAPK effector kinase (MEK) and results in MAPK activation. MAPK phosphorylates,the final effector of the cascade, ERK. The RAS-MAPK pathway is responsible for cell proliferation, cell motility and cell cycle progression 17. A third major downstream axis of MET signaling is the Signal transducer and activator of transcription 3 (STAT3) pathway. STAT3 can bind to MET directly resulting in STAT3 phosphorylation, which regulates cell transformation, tubulogenesis and invasion 10. Finally, the fourth major cascade of MET activation is through the IκBα-NF-κB complex. NF-κB is bound to IκBα forming an inactive form. The phosphorylation of either PI3K-AKT or SRC activates IκB kinase (IKK) and results in degradation of IκBs. NF-κB is then released and translocated to the nucleus to stimulate gene transcription 15.

Bottom Line: Different technologies have been used to investigate the genomic and proteomic status of MET in cancer patients and its association with disease prognosis.We review the molecular mechanisms involved in the deregulation of the MET signaling pathway in solid tumors, the different technologies used for diagnosis, and the main factors that affect the outcome, emphasizing the urge for completing analytical and clinical validation of these tests.We also review the current clinical studies with MET targeted agents, which mostly focus on lung cancer.

View Article: PubMed Central - PubMed

Affiliation: 1. Faculty of Medicine, Chiang Mai University, 110 Intavarorod Rd., Muang, Chiang Mai, Thailand 50200.; 3. Department of Medicine, University of Colorado, Anschutz Medical Campus, 12801 East 17th Ave, RC1 South, L18-8118, Mail Stop 8117, Aurora, Colorado, USA 80045.

ABSTRACT
The MET signaling pathway plays an important role in normal physiology and its deregulation has proved critical for development of numerous solid tumors. Different technologies have been used to investigate the genomic and proteomic status of MET in cancer patients and its association with disease prognosis. Moreover, with the development of targeted therapeutic drugs, there is an urgent need to identify potential biomarkers for selection of patients who are more likely to derive benefit from these agents. Unfortunately, the variety of technical platforms and analysis criteria for diagnosis has brought confusion to the field and a lack of agreement in the evaluation of MET status as a prognostic or predictive marker for targeted therapy agents. We review the molecular mechanisms involved in the deregulation of the MET signaling pathway in solid tumors, the different technologies used for diagnosis, and the main factors that affect the outcome, emphasizing the urge for completing analytical and clinical validation of these tests. We also review the current clinical studies with MET targeted agents, which mostly focus on lung cancer.

No MeSH data available.


Related in: MedlinePlus