Background:
Cardiotoxicity is a major clinical limitation with doxorubicin (DOX). Also, the PI3K/Akt survival pathway is one of the most commonly mutated pathways in cancer. Therefore, the combination of kinase inhibitors and chemotherapy, such as DOX, are necessary for achieving cancer control. The PI3K pathway is also critical for protecting the heart from stress. Therefore, we examined the combined effect of BEZ235 (BEZ), a dual PI3k/mTOR inhibitor, with DOX on cardiac function and killing of breast cancer cells.
Methods and results:
c57 mice were treated with BEZ (40 mg/kg daily oral gavage) and DOX (3 IV injections of 5 mg/kg) either alone or in combination. Systolic function was assessed 12 weeks after initial treatment using echocardiography. Decreased ejection fraction was observed after DOX treatment. Interestingly, the combined treatment with BEZ and DOX did not exacerbate DOX cardiotoxicity (Fig. A). Western blot analysis showed significant increase in AKT (thr 308) and ERK phosphorylation with BEZ and DOX as compared individual treatment with BEZ or DOX in the heart (Fig. B). To address the anti-cancer effects of these drugs, MDA-MB-231 breast cancer cells were treated with BEZ and DOX either alone or in combination for 48 hours. Necrosis, measured using the trypan blue assay, showed a significant increase in dead cells compared to either drug alone (Fig. C).
Conclusion:
Concurrent treatment with DOX and BEZ did not exacerbate cardiac toxicity as demonstrated by similar level of deficit in ejection fraction between DOX as well as DOX plus BEZ. This could be due to enhanced survival signaling in the combination group. BEZ also sensitized breast cancer cells to DOX resulting in increased cell death. We propose that this combination strategy might lead to improved long term outcomes for patients with breast cancer without additional complications related to cardiac dysfunction.
The PI3K/mTOR inhibitor Gedatolisib eliminates dormant breast cancer cells in organotypic culture, but fails to prevent metastasis in preclinical settings
