Heat shock protein 90 inhibitors induce cell differentiation via the ubiquitin-dependent aurora kinase A degradation in a MPLW515L mouse model of primary myelofibrosis.

Primary myelofibrosis (PMF) is characterized by immature megakaryocytic hyperplasia, splenomegaly, extramedullary hematopoiesis and bone marrow fibrosis. Our preclinical study had demonstrated that aurora kinase A (AURKA) inhibitor MLN8237 reduced the mutation burden of PMF by inducing differentiation of immature megakaryocytes. However, it only slightly alleviated splenomegaly, reduced tissue fibrosis, and normalized megakaryocytes in PMF patients of the preliminary clinical study. So enhancing therapeutic efficacy of PMF is needed. In this study, we found that AURKA directly interacted with heat shock protein 90 (HSP90) and HSP90 inhibitors promoted the ubiquitin-dependent AURKA degradation. We demonstrated that HSP90 inhibitors 17-allylamino-17-demethoxygeldanamycin (17-AAG) and 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG), normalized peripheral blood counts, improved splenomegaly, attenuated extramedullary hematopoiesis, decreased tissue fibrosis and reduced mutant burden in a MPLW515L mouse model of PMF. Importantly, both 17-AAG and 17-DMAG treatment at effective doses in vivo did not influence on hematopoiesis in healthy mice. Collectively, the study demonstrates that HSP90 inhibitors induce cell differentiation via the ubiquitin-dependent AURKA and also are safe and effective for the treatment of a MPLW515L mouse model of PMF, which may provide a new strategy for PMF therapy. Further, we demonstrate that combined therapy shows superior activity in acute megakaryocytic leukemia mouse model than single therapy.

Association of Adjuvant Radiation Therapy With Long-Term Overall and Recurrence-Free Survival After Hepatectomy for Hepatocellular Carcinoma: A Multicenter Propensity-Matched Study.

PURPOSE: R0 resection with a wide surgical margin is the gold standard for hepatocellular carcinoma (HCC), yet R0 resection with narrow margins and even R1 resection is not uncommon in real-world clinical practice. We sought to use a propensity-matched analysis to characterize the efficacy of adjuvant radiation therapy on long-term oncological survival after hepatectomy for HCC with narrow or positive margins. METHODS AND MATERIALS: Using a multi-institutional database, patients with HCC who underwent hepatectomy with negative margins of 0.1 to 1.0 cm or pathologically positive margins were analyzed. Using propensity score matching (PSM) and multivariate Cox-regression analysis, the effect of adjuvant radiation therapy on long-term overall survival (OS) and recurrence-free survival (RFS) was evaluated. RESULTS: Among 683 patients who met inclusion criteria, 82 patients received adjuvant radiation therapy within 10 weeks after surgery. Radiation therapy-related major toxic effects were minimal among patients receiving adjuvant radiation therapy. PSM analysis created 78 matched pairs of patients. In the PSM cohort, median OS and RFS among patients treated with adjuvant radiation therapy were more favorable than individuals who were not treated (72.5 and 37.3 months versus 52.5 and 24.0 months, both P < .05). After adjustment for other confounding factors on multivariate analyses, adjuvant radiation therapy remained independently associated with favorable OS and RFS after hepatectomy with close/positive surgical margins for HCC (hazard ratios, 0.821 and 0.827, respectively). CONCLUSIONS: Despite the lack of consensus on the role of adjuvant radiation therapy after HCC resection, this PSM analysis suggested improved OS and RFS with adjuvant radiation therapy after hepatectomy with close/positive surgical margins for HCC. Future randomized controlled trials are needed to further define the survival benefit of adjuvant radiation therapy for patients with HCC.