Targeting Small Cell Lung Cancer Harboring PIK3CA Mutation with a Selective Oral PI3K Inhibitor PF-4989216
Menée sur des lignées cellulaires de cancer du poumon à petites cellules présentant une mutation du gène PI3KCA, cette étude évalue l'activité antitumorale d'un composé appelé PF-4989216, un inhibiteur de PI3K
Purpose: Constitutive activation of PI3K occurs frequently in many human tumors via either gene mutation in the p110alpha catalytic subunit of PI3K or functional loss of tumor suppressor PTEN. Small cell lung cancer (SCLC) patients have very poor prognosis and survival rates such that an effective targeted therapy is in strong demand for these patients. In this study, we characterized the highly selective oral PI3K inhibitor, PF-4989216, in preclinical SCLC models to investigate whether targeting the PI3K pathway is an effective targeted therapy option for SCLCs that harbor a PIK3CA mutation. Experimental Design: A panel of SCLC lines with PIK3CA mutation or PTEN loss were treated with PF-4989216 in several in vitro assays including: PI3K pathway signaling, cell viability, apoptosis, cell cycle progression, and cell transformation. SCLC lines that were sensitive in vitro to PF-4989216 were further evaluated by in vivo animal studies to determine the pharmacokinetic/pharmacodynamic relationship and tumor growth inhibition by PF-4989216 treatment. Results: PF-4989216 inhibited PI3K downstream signaling and subsequently led to apoptosis induction, and inhibition in cell viability, transformation, and xenograft tumor growth in SCLCs harboring PIK3CA mutation. In SCLCs with PTEN loss, PF-4989216 also inhibited PI3K signaling but did not induce BIM-mediated apoptosis nor was there any effect in cell viability or transformation. These results implicate differential tumorigenesis and apoptosis mechanisms in SCLCs harboring PIK3CA mutation versus PTEN loss. Conclusion: Our results suggest that PF-4989216 is a potential cancer drug candidate for SCLC patients with PIK3CA mutation but not PTEN loss.