Activation of tumor suppressor protein PP2A inhibits KRAS-driven tumor growth
Jaya Sangodkar1, Abbey Perl2, Rita Tohme2,3
1Icahn School of Medicine at Mount Sinai, New York, New York, USA.
Abstract:
Targeted cancer therapies, which act on specific cancer-associated molecular targets, are predominantly inhibitors of oncogenic kinases. While these drugs have achieved some clinical success, the inactivation of kinase signaling via stimulation of endogenous phosphatases has received minimal attention as an alternative targeted approach. Here, we have demonstrated that activation of the tumor suppressor protein phosphatase 2A (PP2A), a negative regulator of multiple oncogenic signaling proteins, is a promising therapeutic approach for the treatment of cancers. Our group previously developed a series of orally bioavailable small molecule activators of PP2A, termed SMAPs. We now report that SMAP treatment inhibited the growth of KRAS-mutant lung cancers in mouse xenografts and transgenic models. Mechanistically, we found that SMAPs act by binding to the PP2A Aα scaffold subunit to drive conformational changes in PP2A. These results show that PP2A can be activated in cancer cells to inhibit proliferation. Our strategy of reactivating endogenous PP2A may be applicable to the treatment of other diseases and represents an advancement toward the development of small molecule activators of tumor suppressor proteins.
Insights
Activating protein phosphatase 2A (PP2A) with small molecule activators (SMAPs) shows promise for cancer treatment. SMAP therapy inhibited lung cancer growth by restoring PP2A tumor suppressor function.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Targeted cancer therapies primarily use kinase inhibitors, with limited exploration of phosphatase activation.
- Protein phosphatase 2A (PP2A) is a key tumor suppressor that negatively regulates oncogenic signaling pathways.
Purpose of the Study:
- To investigate the therapeutic potential of activating endogenous PP2A for cancer treatment.
- To evaluate the efficacy of small molecule activators of PP2A (SMAPs) in preclinical cancer models.
Main Methods:
- Development of orally bioavailable SMAPs targeting PP2A.
- Assessment of SMAP efficacy in KRAS-mutant lung cancer xenografts and transgenic mouse models.
- Mechanistic studies involving PP2A scaffold subunit binding and conformational changes.
Main Results:
- SMAP treatment significantly inhibited the growth of KRAS-mutant lung cancers in vivo.
- SMAPs were found to bind the PP2A Aα scaffold subunit, inducing functional conformational changes.
- Reactivation of PP2A demonstrated its role in inhibiting cancer cell proliferation.
Conclusions:
- Activation of the tumor suppressor PP2A via SMAPs is a viable therapeutic strategy for cancer.
- This approach offers a novel targeted therapy by reactivating endogenous tumor suppressor proteins.
- PP2A activation may have broader applications in treating other diseases.
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