366P - Exploring the benefit of combining paclitaxel with capivasertib treatment in PI3K/AKT/PTEN-altered and non-altered TNBC preclinical models

Background

In the Phase II PAKT study in triple negative breast cancer (TNBC) (NCT02423603), addition of capivasertib to first-line paclitaxel resulted in significantly longer progression-free survival (PFS) and overall survival (OS) versus paclitaxel. While activity was observed in PI3K/AKT pathway altered and non-altered tumours slightly greater activity was seen in pathway altered tumours. The paclitaxel/capivasertib combination is being tested in the Phase III CAPItello-290 trial (NCT03997123), as first-line treatment of patients with PIK3CA/AKT1/PTEN-altered and non-altered metastatic TNBC. To understand the contributions of the combination to efficacy in pathway altered and non-altered TNBC the impact in cell line models was assessed.

Methods

To reflect the clinical schedule, cells were dosed with paclitaxel 24 hours prior to treatment with capivasertib. Following pre-treatment with paclitaxel we investigated the effects of capivasertib treatment on PI3K/AKT pathway inhibition, cell survival and proliferation by western blot and cell imaging.

Results

In a panel of TNBC cell lines combining paclitaxel and capivasertib gave increased anti tumour activity. Acute treatment of PIK3CA/AKT1/PTEN-altered and non-altered TNBC cells with paclitaxel resulted in a paclitaxel persister cell population resistant to G2/M cell cycle arrest. Treatment with increasing concentrations of paclitaxel caused a dose dependent increase in phosphorylation of AKT downstream biomarkers including 4E-BP1 and P70S6K in paclitaxel persister cells indicating PI3K/AKT pathway activation. Short term capivasertib treatment reversed pathway activation in paclitaxel persister cells and increased markers of apoptosis whilst long term treatment with capivasertib delayed the outgrowth of paclitaxel persister cells.

Conclusions

Pre-clinical investigations indicate that paclitaxel can activate PI3K/AKT signaling in TNBC cells and that combining capivasertib with paclitaxel treatment inhibits pathway activation resulting in pathway inhibition with decreased cell proliferation and increased cell death. This effect is apparent in cells that are both PIK3CA, AKT1 or PTEN altered and in non-altered cells.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

AstraZeneca.

Funding

AstraZeneca.

Disclosure

C.A. Eberlein: Financial Interests, Personal, Full or part-time Employment: AstraZeneca. L. Vasiliauskaite: Financial Interests, Personal, Full or part-time Employment: AstraZeneca. J. Kerr: Financial Interests, Personal, Full or part-time Employment: AstraZeneca. C. Blaker: Financial Interests, Personal, Full or part-time Employment: AstraZeneca. S. Williamson: Financial Interests, Personal, Full or part-time Employment: AstraZeneca. L. Hopcroft: Financial Interests, Personal, Full or part-time Employment: AstraZeneca. S. Ros: Financial Interests, Personal, Full or part-time Employment: AstraZeneca. J. Moss: Financial Interests, Personal, Full or part-time Employment: AstraZeneca. E. De Bruin: Financial Interests, Personal, Full or part-time Employment: AstraZeneca. C. Rooney: Financial Interests, Personal, Full or part-time Employment: AstraZeneca. B. Willis: Financial Interests, Personal, Full or part-time Employment: AstraZeneca. S. Dunn: Financial Interests, Personal, Full or part-time Employment: AstraZeneca. S. Barry: Financial Interests, Personal, Full or part-time Employment: AstraZeneca.