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PUMA and BIM are required for oncogene inactivation-induced apoptosis
Gregory R Bean1, Yogesh Tengarai Ganesan, Yiyu Dong
1Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
Abstract:
The clinical efficacy of tyrosine kinase inhibitors supports the dependence of distinct subsets of cancers on specific driver mutations for survival, a phenomenon called "oncogene addiction." We demonstrate that PUMA and BIM are the key apoptotic effectors of tyrosine kinase inhibitors in breast cancers with amplification of the gene encoding human epidermal growth factor receptor 2 (HER2) and lung cancers with epidermal growth factor receptor (EGFR) mutants. The BH3 domain containing proteins BIM and PUMA can directly activate the proapoptotic proteins BAX and BAK to permeabilize mitochondria, leading to caspase activation and apoptosis. We delineated the signal transduction pathways leading to the induction of BIM and PUMA by tyrosine kinase inhibitors. Inhibition of the mitogen-activated or extracellular signal-regulated protein kinase kinase (MEK)-extracellular signal-regulated kinase (ERK) pathway caused increased abundance of BIM, whereas antagonizing the phosphoinositide 3-kinase (PI3K)-AKT pathway triggered nuclear translocation of the FOXO transcription factors, which directly activated the PUMA promoter. In a mouse breast tumor model, the abundance of PUMA and BIM was increased after inactivation of HER2. Moreover, deficiency of Bim or Puma impaired caspase activation and reduced tumor regression caused by inactivation of HER2. Similarly, deficiency of Puma impeded the regression of EGFR(L858R)-driven mouse lung tumors upon inactivation of the EGFR-activating mutant. Overall, our study identified PUMA and BIM as the sentinels that interconnect kinase signaling networks and the mitochondrion-dependent apoptotic program, which offers therapeutic insights for designing novel cell death mechanism-based anticancer strategies.
Insights
Tyrosine kinase inhibitors induce cancer cell death by activating PUMA and BIM proteins. These proteins are crucial for tumor regression in HER2-amplified breast and EGFR-mutant lung cancers, offering new therapeutic strategies.
Area of Science:
- Molecular Biology
- Cancer Research
- Cell Death Pathways
Background:
- Cancers often depend on specific driver mutations for survival, a concept known as "oncogene addiction."
- Tyrosine kinase inhibitors (TKIs) are effective against certain cancers, but their precise apoptotic mechanisms require elucidation.
- PUMA and BIM are known pro-apoptotic proteins, but their specific roles in TKI-induced cancer cell death are not fully understood.
Purpose of the Study:
- To identify the key apoptotic effectors of TKIs in HER2-amplified breast and EGFR-mutant lung cancers.
- To delineate the signal transduction pathways responsible for PUMA and BIM induction by TKIs.
- To investigate the therapeutic implications of PUMA and BIM in TKI-mediated cancer regression.
Main Methods:
- Utilized mouse models of HER2-amplified breast cancer and EGFR-mutant lung cancer.
- Inactivated HER2 and EGFR-activating mutants to observe tumor response.
- Assessed the abundance and function of PUMA and BIM proteins.
- Examined the role of MEK-ERK and PI3K-AKT pathways in regulating PUMA and BIM.
- Studied the impact of Bim or Puma deficiency on tumor regression and caspase activation.
Main Results:
- PUMA and BIM were identified as critical apoptotic effectors of TKIs in HER2+ breast and EGFR-mutant lung cancers.
- Inhibition of the MEK-ERK pathway increased BIM abundance, while PI3K-AKT inhibition led to PUMA activation via FOXO transcription factors.
- In HER2-amplified breast cancer models, HER2 inactivation increased PUMA and BIM levels; Bim or Puma deficiency impaired tumor regression.
- In EGFR-mutant lung cancer models, Puma deficiency impeded tumor regression upon EGFR inactivation.
Conclusions:
- PUMA and BIM act as sentinels connecting kinase signaling to mitochondrial apoptosis.
- Targeting PUMA and BIM pathways offers potential for novel anticancer strategies.
- Understanding these pathways provides therapeutic insights for cell death mechanism-based cancer treatments.
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