Findings from a preclinical study of PI3K inhibitor taselisib’s mechanism of action in mutant cell line and breast cancer xenograft models surprised researchers, according to a talk presented at the 2016 San Antonio Breast Cancer Symposium.1

“Taselisib leads to depletion of mutant p100a protein that is dose-dependent and time-dependent,” said lead study author Lori Friedman, PhD, of Genentech, in South San Francisco, California.                            

PIK3CA mutations affect the biology of tumor cell cycle, survival, growth, and proliferation. These mutations are frequently found in human cancers, including ER+, HER2+ and triple-negative breast cancers, Dr Friedman noted.

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PI3K-inhibiting agents are in development but have a narrow therapeutic index; it can be a challenge to balance safety and antitumor activity. They also appear to reduce negative feedback responses upstream in the target tumor pathway, causing PI3K inhibitors’ use to reduce their antitumor activity.

“Feedback and pathway reactivation attenuates the activity of PI3K inhibitors,” she explained. “Most PI3K inhibitors are effective at 1 hour and lose potency at 24 hours.”

But taselisib exhibits stronger activity against tumor cells harboring PIK3CA mutations than other PI3K-targeting agents, Dr Friedman said.

“Taselisib has strong pathway suppression maintained at 24 hours in mutant cells,” Dr Friedman said. “Mutant cells are more sensitive to taselisib than wildtype cells. Taselisib is better at suppressing signaling at 24 hours.”

The research team believes that this suggests taselisib has a unique mechanism of action that mitigates the feedback issue. They hypothesize that taselisib degrades mutant PI3Kα, a “unique” mechanism of action among clinical compounds that might widen its therapeutic index.

“Taselisib is more effective at blocking signaling after feedback; this results in stronger apoptosis and in vivo efficacy for taselisib than other PI3K inhibitors that do not degrade p110a,” Dr Friedman said.

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Taselisib’s strong induction of mutant cell apoptosis is likely due to its reinforcement of “pathway suppression after feedback,” she said. In mice, maximum-tolerated doses induced breast tumor xenograft regressions.


  1. Friedman LS, Edgar KA, Song K, et al. The PI3K inhibitor, taselisib, has enhanced potency in PIK3CA mutant models through a unique mechanism of action. Paper presented at: 39th San Antonio Breast Cancer Symposium; Dec 2016; San Antonio, TX.