Chromosomal Instability (CIN) is regarded as a unifying feature of heterogeneous tumor populations, driving intratumoral heterogeneity. Polo-Like Kinase 1 (PLK1), a serine-threonine kinase that is often overexpressed across multiple tumor types, is one of the key regulators of CIN and is considered as a potential therapeutic target. However, targeting PLK1 has remained a challenge due to the off-target effects caused by the inhibition of other members of the polo-like family. Here we use synthetic dosage lethality (SDL), where the overexpression of PLK1 is lethal only when another, normally non-lethal, mutation or deletion is present. Rather than directly inhibiting PLK1, we found that inhibition of PP2A causes selective lethality to PLK1-overexpressing breast, pancreatic, ovarian, glioblastoma, and prostate cancer cells. As PP2A is widely regarded as a tumor suppressor, we resorted to gene expression datasets from cancer patients to functionally dissect its therapeutic relevance. We identified two major classes of PP2A subunits that negatively correlated with each other. Interestingly, most mitotic regulators, including PLK1, exhibited SDL interactions with only one class of PP2A subunits (PPP2R1A, PPP2R2D, PPP2R3B, PPP2R5B and PPP2R5D). Validation studies and other functional cell-based assays showed that inhibition of PPP2R5D affects both levels of phospho-Rb as well as sister chromatid cohesion in PLK1-overexpressing cells. Finally, analysis of clinical data revealed that patients with high expression of mitotic regulators and low expression of Class I subunits of PP2A improved survival. Overall, these observations point to a context-dependent role of PP2A that warrants further exploration for therapeutic benefits.

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299 Background: Pancreatic cancer is a major cause of cancer-related death. Less than 20% of patients have resectable disease at diagnosis. Patients with borderline-resectable pancreatic cancer (BRPC) are at high risk of incomplete resection with upfront surgery. Currently there is no standard induction chemotherapy regimen exists for BRPC. Both FOLFIRINOX (5-FU, irinotecan, oxaliplatin) and gemcitabine/nab-paclitaxel (GnP) have shown better efficacy than gemcitabine in advanced pancreatic cancer. The current study aims to assess outcomes of real-world patients with BRCP who received induction FOLFIRINOX or GnP. Methods: In this population-based multicenter retrospective cohort study patients with biopsy proven BRPC as defined by the pancreatic surgical team diagnosed from 2011-2017, in the province of Saskatchewan, Canada, who received FOLFIRINOX or GnP were assessed. Kaplan Meier methods and log rank tests were performed for survival analyses. Results: Of 161 patients with pancreatic cancer who received FOLFIRINOX or GnP during the study period, 20 eligible patients with BRPC, with median age of 65 yrs (54-79) and M:F 14:6, were identified. 85% had pancreatic head tumours with a median CA19-9 of 470 u/mL. Of eligible patients, 10 each received FOLFIRINOX or GnP. No significant differences were found between the two groups, except more patients in FOLFIRINOX group had a WHO performance status of 0 (50% vs. 10%, p = 0.057) and had a higher body mass index (27.0 vs. 23.0, p = 0.027). Eleven patients showed partial response (5–FOLFIRINOX and 6–GnP), three progressed during treatment. Five patients (4–FOLFIRINOX, 1–GnP, p = NS) underwent curative surgery. Five patients (1–FOLFIRINOX, 4–Gnp) had radiation and four underwent Nanoknife procedure (3–FOLFIRINOX, 1–GnP). The median progression free survival was 17 months in FOLFIRINOX (95% CI: 5.3-28.6) versus nine months (3.0-15) in GnP group (p = 0.26). The median overall survival was 32 months in FOLFIRINOX (not reach) versus 16 months (9.3-22.7) in GnP group (p = 0.15). Conclusions: The current study suggests that patients with BRPC who received FOLFIRINOX tends to have better outcomes. Future study are warranted to establish a preferred systemic therapy for BRPC.