AUM302

In this study, we evaluate the effect of the novel multikinase PIM/PI3K/mTOR inhibitor, AUM302, and commercially available PIM inhibitor, TP-3654. Significantly, AUM302 had a strong impact on the viability of gemcitabine-resistant PDAC cells. Taken together, these results demonstrate that AUM302 exhibits antitumor activity in human PDAC cells and thus has the potential to be an effective drug for PDAC therapy.

These drugs were AZD-1208, a pan-PIM kinase inhibitor; BEZ235/Dactolisib, a pan-PI3K-mTOR dual inhibitor, a combination of both AZD-1208 and BEZ235, and AUM-302 – a preclinical PIM, PI3K, mTOR triple inhibitor. However, AZD-1208 activated PI3K cascade. MKi67 and PIM genes activity switched between different cell types in response to the different treatments, which may be compensatory.ConclusionWe conclude that pre-clinical drug development can and should be carried out not just on cancer cells but on complex models, including epithelium, stroma, and benign areas, and that when such drug screening is carried out, advanced endpoint analyses such as spatial transcriptomics are warranted, in order to properly assess both the promise and the pitfalls of drug candidates in clinically relevant settings.

Our results demonstrate in vitro efficacy of IBL-302 in a range of breast cancer cell lines, including lines with acquired resistance to trastuzumab and lapatinib. The combination of trastuzumab and IBL-302 significantly increased the anti-proliferative effect in HER2+ breast cancer cell line, and matched trastuzumab-resistant line, relative to testing either drug alone. We thus believe that the novel PIM and PI3K/mTOR inhibitor, IBL-302, represents an exciting new potential treatment option for breast cancer, and that it should be considered for clinical investigation.