In CCNE1 amp tumors, SRA737 showed profound activity as a monotherapy in this PARPi-resistant model. In PARPi-resistant models, SRA737 is active as a monotherapy, and the combination of SRA737 with PARPi demonstrated synergy. Strategies to optimize treatments for PARPi-resistant HGSOC, as well as for platinum-resistant CCNE1 amp HGSOC, are needed. Lastly, in an orthotopic PDX model established from a platinum-resistant CCNE1 amp ovarian cancer patient, SRA737 monotherapy caused significant tumor regression, similar to SRA737 in combination with PARPi. 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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