The effect of combined PI3K/mTOR and ERK inhibition in monolayer, three-dimensional and in vivo ovarian cancer models.

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Theses / Dissertations
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Doctor of Philosophy
University of Canterbury
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Dunn, Elizabeth

Ovarian cancer is a deadly disease for which finding effective treatments has proved challenging. The poor prognosis for this disease has changed little over the past two decades, with 5-year survival rates below 50%. Most patients will initially respond to platinum-based chemotherapies, despite presenting with an advanced stage of the disease. Unfortunately, most of these will eventually relapse and no-longer respond to treatment. Therefore, there is an urgent need for new additional treatment strategies.

The main ovarian cancer subtypes (serous, endometrioid, mucinous and clear cell ovarian carcinoma) typically have mutations in the proteins involved in the PI3K/AKT/mTOR and RAS/RAF/MEK/ERK signalling cascades, which can affect cell proliferation and apoptosis. These proteins are attractive targets for potential therapeutic inhibitors. However, resistance often develops to single inhibitor treatments and they can promote the increased signalling of the adjacent pathway.

Several preclinical studies have demonstrated efficacy with PI3K/mTOR inhibitors, and that efficacy is enhanced by inhibiting MEK. However, there are several mechanisms of acquired resistance to MEK inhibitors. The ERK inhibitor SCH772984 has overcome BRAF and MEK inhibitor resistance in melanoma cell lines. This inhibitor, alone, and in combination with PI3K/AKT/mTOR inhibitors such as BEZ235, has yet to be investigated as a potential ovarian cancer treatment.

In this study the efficacy of combined PI3K/mTOR inhibition (using BEZ235) and ERK inhibition (using SCH772984) was investigated using four human ovarian cancer cell lines and a syngeneic mouse model. The inhibitor combination reduced cellular proliferation in a synergistic manner and there was evidence of an anti-tumour effect in vivo. SCH772984 alone reduced ovarian cancer cell line proliferation. However, the inhibitor combination did not induce apoptosis. The sensitivity of the cell lines to the inhibitors was reduced in three-dimensional cell aggregates.

These findings suggest that combined PI3K/mTOR and ERK inhibition, and ERK inhibition alone, could be a useful strategy for overcoming treatment resistance in ovarian cancer and warrants further preclinical investigation.

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