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Tumor suppressor p53 is inactivated by thousands of heterogeneous mutations in cancer, but their individual druggability remains largely elusive. Here, we evaluated 800 common p53 mutants for their rescue potencies by the representative generic rescue compound arsenic trioxide (ATO) in terms of transactivation activity, cell growth inhibition, and mouse tumor–suppressive activities. The rescue potencies were mainly determined by the solvent accessibility of the mutated residue, a key factor determining whether a mutation is a structural one, and the temperature sensitivity, the ability to reassemble the wild-type DNA binding surface at a low temperature, of the mutant protein. A total of 390 p53 mutants were rescued to varying degrees and thus were termed as type 1, type 2a, and type 2b mutations, depending on the degree to which they were rescued. The 33 type 1 mutations were rescued to amounts comparable to the wild type. In PDX mouse trials, ATO preferentially inhibited growth of tumors harboring type 1 and type 2a mutants. In an ATO clinical trial, we report the first-in-human mutant p53 reactivation in a patient harboring the type 1 V272M mutant. In 47 cell lines derived from 10 cancer types, ATO preferentially and effectively rescued type 1 and type 2a mutants, supporting the broad applicability of ATO in rescuing mutant p53. Our study provides the scientific and clinical communities with a resource of the druggabilities of numerous p53 mutations ( www.rescuep53.net ) and proposes a conceptual p53-targeting strategy based on individual mutant alleles rather than mutation type.

SPAG5, as a spindle-associated protein in mitosis, has been observed to have oncogenic activities in solid tumors. Here, we identified that SPAG5 expression was correlated with the deterioration of plasma cell malignancy and SPAG5 overexpression (OE) predicted unfavorable outcomes in multiple myeloma (MM). SPAG5 knockdown led to anti-MM effects in MM cell lines and animal xenograft models by regulating cell growth and apoptosis. Furthermore, gene set enrichment analysis (GSEA) revealed that PI3K/AKT/mTOR pathway was enriched in MM samples with highly expressed SPAG5 from GSE datasets. There was a concurrent downregulation of phosphorylation levels in the AKT/mTOR pathway. Yet OE of SPAG5 could restore the cell growth and p-AKT levels in MM cells after treatment with the AKT inhibitor MK2206. Taken together, SPAG5 could serve as a novel biomarker, and targeting the SPAG5 might have therapeutic potential in MM.

Objective: Multiple myeloma (MM) remains incurable with high rates of relapse. New therapeutic drugs are therefore urgently needed to improve the prognosis. JaponiconeA (JA), a natural product isolated from Inula japonica Thunb, has shown good anti-MM potential. A comprehensive study should therefore be conducted to identify both the in vitro and in vivo mechanisms of the anti-MM effects of JA. Methods: CCK8 assays and flow cytometry were used to detect the proliferation, apoptosis, and cell cycle of MM cell lines when treated with JA. In vivo experiments were conducted using subcutaneous xenograft mouse models. We also identified possible targets and the mechanism of JA using RNA-seq and c-Map databases, and identified the specific targets of JA in bortezomib-sensitive and -resistant MM cell lines using CETSA, DARTS, and rescue experiments. Furthermore, JA and bortezomib were used separately or together to characterize their possible synergistic effects. Results: In vitro, JA inhibited proliferation, and induced apoptosis and G2/M phase arrest in MM cell lines, and selectively killed primary CD138+ MM cells. In vivo, JA also demonstrated a strong anti-tumor effect with no observable toxicity. In addition, JA showed synergetic effects in combination with bortezomib, and enhanced the anti-tumor effect of bortezomib in bortezomib-resistant cells. CETSA and DARTS confirmed direct binding of JA to NF-κB inhibitor kinase beta (IKKβ), and overexpression of IKKβ or knockdown of IκBα partially rescued the apoptosis induced by JA. Conclusions: JA exhibited strong anti-tumor effects in MM. It sensitized myeloma cells to bortezomib and overcame NF-κB-induced drug resistance by inhibiting IKKβ, providing a new treatment strategy for MM patients.

Multiple myeloma (MM) remains incurable with high rates of relapse. New therapeutic drugs are therefore urgently needed to improve the prognosis. JaponiconeA (JA), a natural product isolated fromCCK8 assays and flow cytometry were used to detect the proliferation, apoptosis, and cell cycle of MM cell lines when treated with JA.JA exhibited strong anti-tumor effects in MM. It sensitized myeloma cells to bortezomib and overcame NF-κB-induced drug resistance by inhibiting IKKβ, providing a new treatment strategy for MM patients.

Backgrounds: Multiple myeloma (MM) is a clonal proliferative disease of abnormal plasma cells. Relapse and drug resistance still remain to be solved, so new therapeutic drugs are needed to be adopted to further improve the prognosis of MM. JaponiconeA (JA) is a natural product isolated from Inula japonica Thunb, the anti-tumor effect and mechanism in MM has not been studied.Methods: CCK8 and flow cytometry were used to detect the proliferation, apoptosis and cell cycle of MM cell lines with JA treatment. And the in vivo effects of JA were verified in the subcutaneous xenograft mice model of MM. In addition, we analyzed the possible targets and mechanism of JA through RNA-seq and c-Map databases, and we verified the specific target of JA in MM cell lines and bortezomib-resistant MM cell line through CETSA and rescue experiments. JA and bortezomib were used separately or together to treat MM cell lines to explore the synergetic effect. Results: In vitro experiments, JA inhibited proliferation, induced apoptosis and G2/M phase arrest of MM cell lines, and JA selectively killed primary CD138+ MM cells but spared normal human mononuclear cells. In vivo experiments, JA also showed good anti-tumor effect with no observable toxicity. In addition, JA achieved good synergetic effect in combination with bortezomib, and enhanced the anti-tumor effect of bortezomib in bortezomib-resistant cells. According to RNA-seq and c-Map data, the target protein of JA might be IKKβ. CETSA experiment confirmed that JA can bind IKKβ directly in vitro, and overexpression of IKKβ could partly rescue the apoptosis induced by JA.Conclusion: JA exhibited strong anti-tumor effects in MM. It sensitized myeloma cells to bortezomib and overcame NF-κB induced drug resistance through inhibiting IKKβ, which providing a new treatment strategy for MM patients.