ABSTRACT
Secondary kinase domain mutations in BCR::ABL1 represent the most common cause of resistance to tyrosine kinase inhibitor (TKI) therapy in chronic myeloid leukemia patients. The first five approved BCR::ABL1 TKIs target the ATP-binding pocket. Mutations confer resistance to these ATP-competitive TKIs and those approved for other malignancies by decreasing TKI affinity and/or increasing ATP affinity. Asciminib, the first highly active allosteric TKI approved for any malignancy, targets an allosteric regulatory pocket in the BCR::ABL1 kinase C-lobe. As a non-ATP-competitive inhibitor, the activity of asciminib is predicted to be impervious to increases in ATP affinity. Here we report several known mutations that confer resistance to ATP-competitive TKIs in the BCR::ABL1 kinase N-lobe that are distant from the asciminib binding pocket yet unexpectedly confer in vitro resistance to asciminib. Among these is BCR::ABL1 M244V, which confers clinical resistance even to escalated asciminib doses. We demonstrate that BCR::ABL1 M244V does not impair asciminib binding, thereby invoking a novel mechanism of resistance. Molecular dynamics simulations of the M244V substitution implicate stabilization of an active kinase conformation through impact on the ï¡-C helix as a mechanism of resistance. These N-lobe mutations may compromise the clinical activity of ongoing combination studies of asciminib with ATP-competitive TKIs.
ABSTRACT
PURPOSE: The present study aimed to investigate the prognostic effect of PD-L1 expressing in tumor and immune cells among patients with esophageal squamous cell carcinoma. PATIENTS AND METHODS: We performed a retrospective cohort study by consecutively recruiting 142 patients. The clinicopathological features and PD-L1 expression on tumor and immune cells were independently evaluated by two pathologists. RESULTS: The median expression rate of PD-L1 was 5% and 30% in tumor and immune cells, respectively. Patients with higher expression of PD-L1 in tumor cells had shorter disease-free and overall survival, and the HRs were 1.52 for relapse (95% CI: 0.88, 2.60) and 1.48 for death (95% CI: 0.82, 2.69). There was no significant association between the PD-L1 expression in immune cells and survival. However, among the patients with PD-L1 expression rate ≤30% in immune cells, the high expression rate of PD-L1 in tumor cells was significantly associated with the relapse and death, with HRs of 2.51 (95% CI: 1.25, 5.06) and 3.51 (95% CI: 1.57, 7.85), respectively. Among patients with PD-L1 expression rate >30% in immune cells, the PD-L1 expression in tumor cells did not show any association with the disease-free and overall survival. CONCLUSION: Our study demonstrates that the integration of PD-L1 expression in tumor and immune cells could be used to predict the relapse and survival among patients with esophageal squamous cell carcinoma.
