Summary Report (chemistry)

Richard Lin, M.D. Departments of Physiology & Biophysics and Medicine Stony Brook University Northport VA Medical Center

Targeting PI 3-kinase signaling for treatment of pancreatic cancer

Kras/PI3K signaling

Does oncogenic Kras requires PI3K to initiate pancreatic tumors

X

Pancreas-specific KrasG12D

Pancreatic tumors Pancreatic tumors?

Pik3caflox/flox (p110α) or Pik3cbflox/flox (p110β)

Pancreas-specific KrasG12D + Pik3ca-/- or Pik3cb-/-

Wu et al. PI3K regulation of RAC1 is required for KRAS-induced

pancreatic tumorigenesis in mice. Gastroenterology 2014; 147:1305

No tumors in Pik3ca-/- pancreas

Summary

• The sustained acinar-to-ductal transformation during tumor formation requires PI3K signaling to Rac1

• Inhibition of PI3K signaling completely blocks Kras-induced pancreatic tumor formation

Already established pancreatic tumors require PI3K signaling

to survive?

KrasG12D/Trp53R172H (KPC) pancreatic cancer cells

Summary

• Inhibition of PI3K signaling prevents the development of pancreatic tumors

• Inhibition of PI3K signaling up-regulates an immunological signature in pancreatic tumor cells that allows T cells recognition and killing

• Systemic inhibition of PI3K signaling has immunosuppressive effects, especially on T cell function

• Strategies that target PI3K signaling in pancreatic cancer cells but not T cells will be needed to treat pancreatic cancer based on this immunological finding