![]() ![]() Consistent with in vitro activity, SRA737 inhibited tumor growth in an OVCAR3 xenograft model. Preliminary evidence in a PARPi resistant PDX model demonstrated tumor growth inhibitory activity of SRA737 in combination with PARPi. SRA737 was also evaluated in a PARPi-resistant PDX model as well as in CCNE1 amp in vivo mouse models. ![]() Furthermore, treatment with SRA737 induced gH2AX (indicator of DNA damage) which increased modestly in combination with PARPi. SRA737 treatment led to a dose-dependent increase in the replication stress marker pCHK1 (S345), confirming an on-target drug effect in PARPi-resistant (PEO1-PR) and CCNE1 amp (OVCAR3) cells. Additionally, the combination of SRA737 with PARPi was synergistic in decreasing colony formation in HR-deficient (PEO1, best coefficient of drug interaction (CDI)=0.53 JHOS4, CDI=0.45) and PARPi-resistant cell models (PEO1-PR, CDI=0.11 PEO4, CDI=0.08). In colony formation assays, SRA737 monotherapy decreased cell survival in HR-deficient, PARPi-resistant and CCNE1 amp cells. We hypothesized that Chk1 inhibition by SRA737 will result in increased replication stress, inducing subsequent cell death and tumor regression in both PARPi-resistant and CCNE1 amp ovarian cancer models. HR-deficiencies and CCNE1 amp are known to increase replication stress, leading to increased reliance on Chk1, a key regulator of cell cycle progression and the replication stress response. Here, we investigated the anti-tumor activity of the potent, highly selective, orally bioavailable small molecule inhibitor of Checkpoint kinase 1 (Chk1), SRA737, in both acquired PARPi-resistant and CCNE1 amp HGSOC models. CCNE1 amp HGSOC show resistance to PARPi and platinum treatments. HR-deficient HGSOC are initially sensitive to Poly(ADP-ribose) polymerase inhibitors (PARPi) but drug resistance ultimately emerges. ![]() High grade serous ovarian cancers (HGSOC) have defective homologous recombination (HR) genes in 50% of cases, while a distinct 20% demonstrate CCNE1 amplification ( CCNE1 amp). ![]()
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