Inactivation of PP2A by a recurrent mutation drives resistance to MEK inhibitors

Area of Science:

• Molecular biology
• Cancer research
• Biochemistry

Background:

• Protein Phosphatase 2A (PP2A) is a tumor suppressor regulating oncogenic pathways.
• The PP2A holoenzyme consists of scaffolding (A), catalytic (C), and regulatory (B) subunits.
• Mutations in PPP2R1A, encoding the PP2A Aα scaffolding subunit, are found in various cancers.

Purpose of the Study:

• To investigate the functional impact of the most common Arg-183 missense mutation (R183W) in the PP2A Aα scaffolding subunit.
• To determine how the R183W mutation affects PP2A holoenzyme composition and function.
• To assess the role of the R183W mutation in tumorigenesis and drug sensitivity.

Main Methods:

• Utilized cellular and in vivo models to study wild-type and R183W mutant PP2A Aα.
• Analyzed holoenzyme formation by assessing regulatory subunit binding.
• Evaluated tumor growth, MAPK pathway activation, and sensitivity to MEK inhibitors.

Main Results:

• The R183W mutation led to the formation of alternative PP2A holoenzymes with altered regulatory subunit composition.
• Wild-type PP2A Aα suppressed tumor growth, whereas the R183W mutant failed to do so in vivo.
• R183W expression activated the MAPK pathway in RAS-mutant cells, increasing tumor growth and reducing sensitivity to MEK inhibitors.

Conclusions:

• The R183W mutation in PP2A Aα abrogates its tumor suppressive functions.
• This mutation potentiates oncogenic signaling by activating the MAPK pathway.
• PP2A Aα R183W mutations confer resistance to MEK inhibitors in RAS-mutant cancers, highlighting a new therapeutic vulnerability.