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Ref Type | Journal Article | ||||||||||||
PMID | (21415220) | ||||||||||||
Authors | Zandi R, Selivanova G, Christensen CL, Gerds TA, Willumsen BM, Poulsen HS | ||||||||||||
Title | PRIMA-1Met/APR-246 induces apoptosis and tumor growth delay in small cell lung cancer expressing mutant p53. | ||||||||||||
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Abstract Text | Small cell lung cancer (SCLC) is a highly malignant disease with poor prognosis, necessitating the need to develop new and efficient treatment modalities. PRIMA-1(Met) (p53-dependent reactivation of massive apoptosis), also known as APR-246, is a small molecule, which restores tumor suppressor function to mutant p53 and induces cancer cell death in various cancer types. Since p53 is mutated in more than 90% of SCLC, we investigated the ability of PRIMA-1(Met) to induce apoptosis and inhibit tumor growth in SCLC with different p53 mutations.The therapeutic effect of PRIMA-1(Met)/APR-246 was studied in SCLC cells in vitro using cell viability assay, fluorescence-activated cell-sorting analysis, p53 knockdown studies, and Western blot analyses. The antitumor potential of PRIMA-1(Met)/APR-246 was further evaluated in two different SCLC xenograft models.PRIMA-1(Met)/APR-246 efficiently inhibited the growth of the SCLC cell lines expressing mutant p53 in vitro and induced apoptosis, associated with increased fraction of cells with fragmented DNA, caspase-3 activation, PARP cleavage, Bax and Noxa upregulation and Bcl-2 downregulation in the cells. The growth suppressive effect of PRIMA-1(Met)/APR-246 was markedly reduced in SCLC cell lines transfected with p53 siRNA, supporting the role of mutant p53 in PRIMA-1(Met)/APR-246-induced cell death. Moreover, in vivo studies showed significant antitumor effects of PRIMA-1(Met) after i.v. injection in SCLC mouse models with no apparent toxicity.This study is the first to show the potential use of p53-reactivating molecules such as PRIMA-1(Met)/APR-246 for the treatment of SCLC. |
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Molecular Profile | Indication/Tumor Type | Response Type | Therapy Name | Approval Status | Evidence Type | Efficacy Evidence | References |
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TP53 S241F | lung small cell carcinoma | sensitive | APR-246 | Preclinical - Cell line xenograft | Actionable | In a preclinical study, APR-246 demonstrated efficacy in xenograft models of small cell lung cancer harboring TP53 S241F (PMID: 21415220). | 21415220 |
TP53 R273L | lung small cell carcinoma | sensitive | APR-246 | Preclinical - Cell line xenograft | Actionable | In a preclinical study, APR-246 demonstrated efficacy in cell line xenograft models of small cell lung cancer harboring TP53 R273L (PMID: 21415220). | 21415220 |
TP53 inact mut | lung small cell carcinoma | sensitive | APR-246 | Preclinical - Cell line xenograft | Actionable | In a preclinical study, APR-246 induced apoptosis in small-cell lung cancer (SCLC) cell lines and decreased tumor growth in SCLC cell line xenograft models harboring Tp53 inactivating mutations (PMID: 21415220). | 21415220 |