PIK3CA mutations can initiate pancreatic tumorigenesis and are targetable with PI3K inhibitors

Area of Science:

• Oncology
• Molecular Biology
• Cancer Pathogenesis

Background:

• Aberrations in the phosphoinositide 3-kinase (PI3K) pathway are implicated in numerous cancers.
• PIK3CA mutations, leading to a constitutively active PI3K, are found in a subset of pancreatic cancers.
• Targeting the PI3K signaling cascade is an active area of clinical research.

Purpose of the Study:

• To investigate PIK3CA-mutant pancreatic tumorigenesis.
• To evaluate the efficacy of dual PI3K/mammalian target of rapamycin (mTOR) inhibition in PIK3CA-mutant pancreatic cancers.
• To examine the role of ERK1/2 signaling in these models.

Main Methods:

• Generation of two murine models expressing constitutively active PI3K in the pancreas.
• Histopathological analysis of pancreatic lesions, including acinar-to-ductal metaplasia and pancreatic intraepithelial neoplasms (PanINs).
• Assessment of invasive pancreatic ductal adenocarcinoma development and response to dual PI3K/mTOR inhibition.
• Investigation of ERK1/2 phosphorylation in pre-neoplastic and neoplastic lesions.

Main Results:

• Constitutively active PI3K induced rapid acinar-to-ductal metaplasia and PanINs, progressing to invasive pancreatic ductal adenocarcinoma.
• Murine pancreatic cancers exhibited high sensitivity to dual PI3K/mTOR inhibition.
• ERK1/2 phosphorylation was observed in pre-neoplastic lesions and invasive cancers, and this activation was reduced by dual PI3K/mTOR inhibition.
• Tumorigenesis and progression showed variable latency depending on the degree of PI3K pathway activation.

Conclusions:

• PIK3CA mutations can initiate pancreatic tumorigenesis.
• PIK3CA-mutant pancreatic cancers are highly sensitive to dual PI3K/mTOR inhibition.
• Dual PI3K/mTOR inhibition also impacts associated ERK1/2 signaling.
• Further investigation of PI3K pathway inhibitors in PIK3CA-mutant pancreatic cancer patients is warranted.