5 research outputs found
Tumor growth inhibitionāoverall survival modeling in nonāsmall cell lung cancer: A case study from GEMSTONEā302
Abstract Overall survival is vital for approving new anticancer drugs but is often impractical for earlyāphase studies. The tumor growth inhibitionāoverall survival (TGIāOS) model could bridge the gap between earlyā and lateāstage development. This study aimed to identify an appropriate TGIāOS model for patients with nonāsmall cell lung cancer from the GEMSTONEā302 study of sugemalimab. We used three TGI models to delineate tumor trajectories and investigated three OS model for linking TGI metric to OS. All three TGI models accurately captured tumor profiles at the individual level. The published atezolizumabābased TGIāOS model predicted survival time satisfactorily through simulationābased evaluation, whereas the other published model built from multiātreatment underestimated OS. Our studyāspecific TGIāOS model identified timeātoāgrowth as the most significant metric with the number of metastatic sites and neutrophilātoālymphocyte ratio at baseline as covariates and exhibited robust OS predictability. Our findings demonstrated the effectiveness of the TGIāOS models in predicting phase III outcomes, which underpins their value as a powerful tool for antitumor drug development
90-kDa Heat Shock Protein Inhibition Abrogates the Topoisomerase I Poison-Induced G2/M Checkpoint in p53-Null Tumor Cells by Depleting Chk1 and Wee1Sā
The G2/M cell cycle checkpoint is regulated by a multitude of
signaling pathways after genotoxic stress. Herein, we report that treatment
with the 90-kDa heat shock protein (Hsp90) molecular chaperone inhibitor
17-allylamino-17-demethoxygeldanamycin (17AAG) selectively abrogates the
G2/M checkpoint induced by 7-ethyl-10-hydroxycamptothecin (SN-38),
an active metabolite of irinotecan, in p53-null compared with p53-intact
HCT116 colon cancer cells. The basis for this selectivity can be explained in
part by the lack of p21 induction in p53-null cells. In accord with published
results, we could show that treatment with 17AAG resulted in depletion of
Chk1, a known Hsp90 client protein. In addition, we observed a time- and
dose-dependent decrease in Wee1 kinase level, a negative regulator of mitosis,
after 17AAG treatment in gastrointestinal cancer cells. Depletion of Wee1
protein preceded mitotic entry induced by 17AAG, and this decrease could be
partially rescued by cotreatment with a proteasome inhibitor.
Coimmunoprecipitation experiments showed that Hsp90 and Wee1 interacted in
whole cells, and 17AAG treatment decreased the degradative half-life of Wee1,
indicating that Wee1 is another Hsp90 client in mammalian cells. Knockdown of
Chk1 and Wee1 by short interfering RNA each resulted in abrogation of the
G2/M checkpoint induced by SN-38. The combination of SN-38 and
17AAG was shown to be synergistic in p53-null but not in parental HCT116 cells
by median effect/combination index analysis. Taken together, 17AAG
specifically inhibits the G2/M checkpoint in p53-defective cells by
down-regulation of two critical checkpoint kinases, Chk1 and Wee1
Aurora B Kinase Regulates the Postmitotic Endoreduplication Checkpoint via Phosphorylation of the Retinoblastoma Protein at Serine 780
The phenotypic change characteristic of Aurora B inhibition is the induction of polyploidy. Utilizing specific siRNA duplexes and a selective small molecule inhibitor (AZD1152) to inhibit Aurora B activity in tumor cells, we sought to elucidate the mechanism by which Aurora B inhibition results in polyploidy. Cells treated with AZD1152 progressed through mitosis with misaligned chromosomes and exited without cytokinesis and subsequently underwent endoreduplication of DNA despite activation of a p53-dependent pseudo G1 checkpoint. Concomitant with polyploid cell formation, we observed the appearance of Rb hypophosphorylation, an event that occurred independently of cyclin-dependent kinase inhibition. We went on to discover that Aurora B directly phosphorylates Rb at serine 780 both in vitro and in vivo. This novel interaction plays a critical role in regulating the postmitotic checkpoint to prevent endoreduplication after an aberrant mitosis. Thus, we propose for the first time that Aurora B determines cellular fate after an aberrant mitosis by directly regulating the Rb tumor suppressor protein