The FACT inhibitor CBL0137 Synergizes with Cisplatin in Small-Cell Lung Cancer by Increasing NOTCH1 Expression and Targeting Tumor-Initiating Cells

Abstract

Traditional treatments of small cell lung cancer (SCLC) with cisplatin, a standard of care therapy, spare the tumor-initiating cells (TIC) that mediate drug resistance. Here we report a novel therapeutic strategy that preferentially targets TIC in SCLC in which cisplatin is combined with CBL0137, an inhibitor of the histone chaperone facilitates chromatin transcription (FACT), which is highly expressed in TIC. Combination of cisplatin and CBL0137 killed patient-derived and murine SCLC cell lines synergistically.In response to CBL0137 alone, TIC were more sensitive than non-TIC, in part because CBL0137 increased expression of the tumor suppressor NOTCH1 by abrogating the binding of negative regulator SP3 to the NOTCH1 promoter, and in part because treatment decreased the high expression of stem cell transcription factors. The combination of cisplatin and CBL0137 greatly reduced the growth of a patient-derived xenograft in mice and also the growth of a syngeneic mouse SCLC tumor. Thus, CBL0137 can be a highly effective drug against SCLC, especially in combination with cisplatin. Statement of SignificanceFindings reveal a novel therapeutic regimen for SCLC combining cisplatin with an inhibitor that preferentially targets tumor-initiating cells.

Potent antileukemic activity of curaxin CBL0137 against MLL‐rearranged leukemia

“…15,23,24 C-trapping induced by CBL0137 exhausts cellular FACT, thereby preventing the protein from exerting its normal functions in transcription, replication and DNA damage repair in cancer cells. [14][15][16]19 We have also previously shown that Ctrapping of FACT subsequently induces two additional, potent antitumor responses that contribute to the anticancer actions of CBL0137, namely p53 activation and inhibition of the NFκB pathway. [14][15][16]19 We have also previously shown that Ctrapping of FACT subsequently induces two additional, potent antitumor responses that contribute to the anticancer actions of CBL0137, namely p53 activation and inhibition of the NFκB pathway.…”

“…14 The synergy between DNA-damage inducing agents and CBL0137 was demonstrated to be caused by an inhibition of FACTmediated DNA repair by CBL0137. 18,19,51 Based on the mechanism of action of CBL0137 in MLL-r leukemia in vivo, it will be worthwhile combining the compound with other targeted approaches against MLL-r leukemia which are currently being tested in clinical trials, with a view to lower chemotherapeutic doses further and potentially enhance safety. Enhancement between CBL0137 and an induction-type treatment regimen that included vincristine was also evident, but its mechanism is less clear.…”

“…[13][14][15][16][17][18][19] CBL0137 acts through a novel, nongenotoxic anticancer mechanism that is based on inducing chromatin disassembly in cells without causing DNA damage, thereby triggering several pathways with anticancer effects. [13][14][15][16][17][18][19] CBL0137 acts through a novel, nongenotoxic anticancer mechanism that is based on inducing chromatin disassembly in cells without causing DNA damage, thereby triggering several pathways with anticancer effects.…”

Histone chaperone HIRA dictate proliferation vs differentiation of chronic myeloid leukemia cells

“…So, HIRA could be targeted as a molecule for enhancing the count in megakaryocytes/platelets, in cases of chronic thrombocytopenia, without causing a total inhibition in the generation of erythrocytes. Recently, a small molecule CBL0137 has been shown to inhibit the function of histone chaperone Facilitates Chromatin Transcription (FACT) and along with cisplatin, could kill patient‐derived and murine small‐cell lung cancer cell lines synergistically . Use of histone chaperone FACT inhibitor preferentially killed glioblastoma stem cells and could prolong the survival in preclinical models .…”

“…Recently, a small molecule CBL0137 has been shown to inhibit the function of histone chaperone Facilitates Chromatin Transcription (FACT) and along with cisplatin, could kill patient-derived and murine small-cell lung cancer cell lines synergistically. 23 Use of histone chaperone FACT inhibitor preferentially killed glioblastoma stem cells and could prolong the survival in preclinical models. 24 Similarly, we anticipate that HIRA could be exploited, as a target for successfully approaching the differentiation therapy in leukemia, provided the full mechanism on how it could affect the normal cells is fully understood.…”