Use of Defined Mutations in TNBC to Enable Patient Selection for PLK1 Inhibitor Therapy.

e12559 Background: PLK1 inhibition has been shown preclinically to impact a number of tumor types. However, other than in AML (Döhner et al 2014), early clinical experience has yielded uniformly modest results. More recent studies indicate that PLK1 inhibition may yield greater responses in specific genetic subtypes. PLK1 has been implicated in promoting growth and survival in cooperation with MYC, PTEN-loss, the PI3K/mTOR pathway and AR signaling (Zhang et al 2014, Hou et al 2013, Liu et al 2011 and Tan et al 2013).We tested whether the selective PLK1 inhibitor P937 could differentially inhibit growth of a genetically diverse panel of TNBC PDX models, enabling selection of a potentially higher responding patient population. Methods: Ten genetically described TNBC PDX models were tested for sensitivity to P937. After implantation and establishment in SCID mice (n = 3 per group), P937 was administered over a 24-day treatment period. Body weight, tumor growth and growth delay after end of treatment were measured. Results: Nine models were evaluable and significant tumor growth inhibition (50-90%) was noted in four. Mutations in responding models have been proposed to enhance sensitivity to PLK1 inhibition in other tumor types, but not previously in TNBC. All lines with sensitivity-enhancing mutations responded while lines without did not. In the most sensitive model, P937 caused uniform, near-complete regressions that were stable for 21 days after final dosing, with minimal body weight loss. Further characterization of all models will be provided. Conclusions: This study appears to be the first report of a PLK1 inhibitor evaluation in a diverse panel of genetically-characterized models in any tumor type. Our results demonstrate that differentially sensitive molecular subtypes of TNBC can be identified and that underlying genetic profiles can be exploited to identify TNBC patients who may benefit most from PLK1 inhibitor therapy. We are continuing to refine the selection criteria as well as to explore additional predictive genetic markers of P937 sensitivity in TNBC and planning for a clinical trial in selected TNBC patients. We believe these results are also extensible into other indications that display these mutations.