Naturally occurring neomorphic PIK3R1 mutations activate the MAPK pathway, dictating therapeutic response to MAPK...

Area of Science:

• Oncology
• Molecular Biology
• Cancer Genetics

Background:

• The phosphoinositide 3-kinase (PI3K) pathway, regulated by PIK3R1 (p85α subunit), is frequently altered in various cancers.
• Mutations in PIK3R1 are common drivers in tumorigenesis, but their functional consequences and therapeutic implications are not fully understood.

Purpose of the Study:

• To investigate the functional impact of specific PIK3R1 mutations, particularly R348∗ and L370fs, on cellular signaling and drug sensitivity.
• To explore the potential of targeting MEK and JNK pathways in cancers harboring these PIK3R1 alterations.

Main Methods:

• In vitro and in vivo experiments were conducted using cell lines and animal models with PIK3R1 mutations.
• Analysis of JNK and ERK phosphorylation levels.
• Subcellular localization studies of PIK3R1 mutants.
• Assessment of sensitivity to MEK and JNK inhibitors.

Main Results:

• PIK3R1(R348∗) and PIK3R1(L370fs) mutations confer sensitivity to MEK and JNK inhibitors, unlike wild-type PIK3R1 or mutations in other regions.
• These mutations lead to increased JNK and ERK phosphorylation.
• PIK3R1 R348∗ and L370fs mutants were found in the nucleus, acting as scaffolds to activate the JNK pathway.

Conclusions:

• PIK3R1(R348∗) and L370fs mutations exhibit a neomorphic function, promoting nuclear JNK pathway activation.
• These findings provide a mechanistic basis for targeting MEK and JNK pathways in tumors with these specific PIK3R1 mutations.