Targeting the MYC Oncogene in Burkitt Lymphoma through HSP90 Inhibition

Abstract

Overexpression of the MYC oncogene is a key feature of many human malignancies including Burkitt lymphoma. While MYC is widely regarded to be a promising therapeutic target, a clinically effective MYC inhibitor is still elusive. Here, we report an alternative strategy, targeting MYC indirectly through inhibition of the HSP90 machinery. We found that inhibition of HSP90 function reduces MYC expression in human Burkitt lymphoma through suppression of MYC transcription and destabilization of MYC protein, thereby diminishing the proliferation of tumor cells. Consistently, treatment of Burkitt lymphoma cell lines with HSP90 inhibitors (17-AAG or 17-DMAG) was accompanied by downregulation of canonical MYC target genes. Combination treatment with 17-DMAG and the proteasome inhibitor, MG-132, led to accumulation of MYC protein, indicating that upon HSP90 inhibition, MYC is degraded by the proteasome. Using co-immunoprecipitation, we furthermore demonstrated a direct interaction between MYC and HSP90, indicating that MYC is an HSP90 client protein in Burkitt lymphoma. Together, we report here the use of HSP90 inhibitors as an alternative approach to target the MYC oncogene and its network in Burkitt lymphoma.

A Driver Never Works Alone—Interplay Networks of Mutant p53, MYC, RAS, and Other Universal Oncogenic Drivers in Human Cancer

“…HSP90 family chaperones were most often discussed in the context of cancer as some of HSP90’s known substrates are oncogenic protein kinases such as SRC, FAK, MET, EGFR, HER2 [ 145 , 146 , 147 ] as well as the telomerase [ 148 ] and the other main oncogenic drivers. These are supported either indirectly, as KRAS in the context of lung cancer [ 149 ], or as direct client proteins of the HSP chaperones, as CMYC in lymphomas [ 150 , 151 ] and p53 in numerous neoplasias. Interestingly, the HSP chaperone stabilization effect on mutant p53 is most likely a side effect of stalling the chaperone machinery normally supporting WT p53 on the intrinsically unstable missense p53 mutants, as described earlier in the section about TP53 mutants [ 22 , 24 , 25 ].…”

Therapeutic Inhibition of Myc in Cancer. Structural Bases and Computer-Aided Drug Discovery Approaches

“…In the latter category, JQ1 was the first reported compound to inhibit Myc-associated chromatin remodeling enzyme Brd4 [86], followed by novel BET inhibitors, such as ZEN-3694, which entered clinical trials and demonstrated efficacy in a variety of solid tumors and hematological malignancies, alone or in combination with several standards [87], and more recent OTX015 [88] and TEN-010 [89]. Indirect suppression of MYC transcription and destabilization of the Myc protein in human Burkitt’s lymphoma has been recently achieved by targeting the Myc-HSP90 axis with HSP90 inhibitors (i.e., 17-AAG or 17-DMAG) [90]. Moreover, indirect synthetically lethal approaches have been reported.…”

Design, Synthesis and Biochemical Evaluation of Novel Ethanoanthracenes and Related Compounds to Target Burkitt’s Lymphoma

“…Amidinopiperidine-based serine protease inhibitor 7 has been reported as a selective inducer of apoptosis in BL cells [17]. The functional overexpression and the pathogenetic role of the MYC proto-oncogene in BL is established [18], indicating the potential role of direct and indirect MYC inhibitors as new experimental therapies [19].Our previous research reported the antidepressant drug maprotiline 8 (Figure 1) as an anti-proliferative and pro-apoptotic agent in BL cell lines 21]. The serotonin transporter (SERT) has been identified in B-cell malignancies; subsequently antidepressants and structurally related compounds were investigated for potential antileukemia/antilymphoma activity [22].…”

“…Amidinopiperidine-based serine protease inhibitor 7 has been reported as a selective inducer of apoptosis in BL cells [17]. The functional overexpression and the pathogenetic role of the MYC proto-oncogene in BL is established [18], indicating the potential role of direct and indirect MYC inhibitors as new experimental therapies [19].…”

“…19. (E)-9-(2-Nitrovinyl)-13-phenyl-9,10-dihydro-9,10-[3,4]epipyrroloanthracene-12,14-dione (16a)Compound 16a was prepared from (E)-9-(2-nitrovinyl)anthracene 12a (0.25 g, 1 mmol) and phenylmaleimide (0.23 g, 1.3 mmol) as described in general procedure 3, to give the product as a colourless solid 126 mg (30%), Mp.…”