Cytokinetically quiescent (G0/G1) human multiple myeloma cells are susceptible to simultaneous inhibition of Chk1 and MEK1/2

Pei, Xin-Yan; Dai, Yun; Youssefian, Leena E.; Chen, Shuang; Bodie, Wesley W.; Takabatake, Yukie; Felthousen, Jessica; Almenara, Jorge A.; Kramer, Lora B.; Dent, Paul; Grant, Steven

doi:10.1182/blood-2011-02-339432

Cited by 43 publications

(46 citation statements)

References 48 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Many inhibitors targeting DNA repair pathways (PARP1, DNA-PK, ATM, ATR, MGMT, APE) or cell-cycle checkpoints (CHK1, CHK2) have now been developed and might be useful to induce tumor cell apoptosis in combination with DNA damage-inducing drugs. [25][26][27][28][29][30] Herein, to further investigate the mechanistic basis for the link between DNA repair efficiency and response to antimyeloma therapy, we studied major DNA repair mechanisms in MM cell lines and malignant bone marrow plasma cells (BMPCs) from patients with MM before antimyeloma therapy. We found that BMPCs from responders to melphalan therapy are characterized by slower rates of NER and DSBs repair (DSB/R) compared with nonresponders.…”

Section: Introductionmentioning

confidence: 99%

DNA repair of myeloma plasma cells correlates with clinical outcome: the effect of the nonhomologous end-joining inhibitor SCR7

Γκοτζαμανίδου

Terpos

Bamia

et al. 2016

Blood

View full text Add to dashboard Cite

Key Points• Responders to melphalan therapy are characterized by slower rates of NER and DSB/R mechanisms and higher apoptotic rates.• The DSB/R inhibitor SCR7 enhances cytotoxicity of melphalan against myeloma plasma cells.DNA repair activity of malignant cells seems to influence therapeutic outcome and patients' survival. Herein, we investigated the mechanistic basis for the link between DNA repair efficiency and response to antimyeloma therapy. Nucleotide excision repair (NER), interstrand cross-links repair (ICL/R), double-strand breaks repair (DSB/R), and chromatin structure were evaluated in multiple myeloma (MM) cell lines (melphalan-sensitive RPMI8226; melphalan-resistant LR5) and bone marrow plasma cells (BMPCs) from MM patients who responded (n 5 17) or did not respond (n 5 9) to subsequent melphalan therapy. The effect of DSB/R inhibition was also evaluated. Responders' BMPCs showed slower rates of NER and DSB/R (P < .0022), similar rates of ICL/R, and more condensed chromatin structure compared with nonresponders. Moreover, apoptosis rates of BMPCs were inversely correlated with individual DNA repair efficiency and were higher in responders' cells compared with those of nonresponders (P 5 .0011). Similarly, RPMI8226 cells showed slower rates of NER and DSB/R, comparable rates of ICL/R, more condensed chromatin structure, and higher sensitivity than LR5 cells. Interestingly, cotreatment of BMPCs or cell lines with DSB/R inhibitors significantly reduced the rates of DSB/R and increased melphalan sensitivity of the cells, with the nonhomologous end-joining inhibitor SCR7 showing the strongest effect. Together, responders' BMPCs are characterized by lower efficiencies of NER and DSB/R mechanisms, resulting in higher accumulation of the extremely cytotoxic ICLs and DSBs lesions, which in turn triggers the induction of the apoptotic pathway. Moreover, the enhancement of melphalan cytotoxicity by DSB/R inhibition offers a promising strategy toward improvement of existing antimyeloma regimens. (Blood. 2016;128(9):1214-1225

show abstract

Section: Introductionmentioning

confidence: 99%

DNA repair of myeloma plasma cells correlates with clinical outcome: the effect of the nonhomologous end-joining inhibitor SCR7

Γκοτζαμανίδου

Terpos

Bamia

et al. 2016

Blood

View full text Add to dashboard Cite

show abstract

“…8,9 We have published several studies combining SRC/MEK1/2 inhibitors with CHK1 inhibitors in established tumor cell types, notably breast cancer cells, but not in CNS tumor cells that are generally thought to be much more resistant to many therapeutic modalities, and demonstrated that the lethality of CHK1 inhibitors is enhanced by their combination with inhibitors of the SRC-RAS-MEK1/2-ERK1/2 pathway. [9][10][11][12][13][14] Treatment of tumor cells with CHK1 inhibitors enhances signaling through the SRC-RAS-MEK1/2-ERK1/2 pathway and expression of a dominant negative CHK1 protein elevates basal ERK1/2 activity and blocks CHK1 inhibitor-induced ERK1/2 activation. [9][10][11][12][13][14] Interruption of MEK1/2-ERK1/2 pathway by MEK1/2 inhibitors dramatically potentiated UCN-01-induced cell death.…”

Section: Introductionmentioning

confidence: 99%

“…[9][10][11][12][13][14] Treatment of tumor cells with CHK1 inhibitors enhances signaling through the SRC-RAS-MEK1/2-ERK1/2 pathway and expression of a dominant negative CHK1 protein elevates basal ERK1/2 activity and blocks CHK1 inhibitor-induced ERK1/2 activation. [9][10][11][12][13][14] Interruption of MEK1/2-ERK1/2 pathway by MEK1/2 inhibitors dramatically potentiated UCN-01-induced cell death. 15,16 What is perhaps more of note are findings that non-transformed blood cells, e.g., peripheral mononuclear cells, CD34 + stem cells or primary cultures of human mammary epithelial cells or of rodent hepatocytes were resistant to the CHK1 inhibitor based drug combination toxicity.…”

Section: Introductionmentioning

confidence: 99%

“…15,16 What is perhaps more of note are findings that non-transformed blood cells, e.g., peripheral mononuclear cells, CD34 + stem cells or primary cultures of human mammary epithelial cells or of rodent hepatocytes were resistant to the CHK1 inhibitor based drug combination toxicity. 10,17 In myeloma blasts freshly isolated from patients, cells that CHK1 inhibitors to kill semi-established isolates of primary human glioblastoma cells. Unlike commercial established cell lines, these isolates exhibit a highly invasive phenotype when grown in the brains of athymic mice that is identical to the disease found in patients.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Enhancing CHK1 inhibitor lethality in glioblastoma

Tang

Dai

Grant

et al. 2012

Cancer Biology & Therapy

Self Cite

View full text Add to dashboard Cite

“…Because the RAS/MEK/ ERK pathway is known to be important for cancer cell signaling and survival, MEK targeting may inhibit the growth of some malignant cells resistant to transplant conditioning in the critical early interval after transplantation. Indeed, recent studies of acute myeloid leukemia, 37 multiple myeloma, 38 cutaneous T-cell lymphomas 39 and diffuse large B-cell lymphoma 40 have demonstrated that MEK inhibition may have significant therapeutic value as antineoplastic agents in the setting of hematologic malignancies known to be responsive to allogeneic SCT.…”

mentioning

confidence: 99%

MEK inhibitors selectively suppress alloreactivity and graft-versus-host disease in a memory stage-dependent manner

Shindo

Kim

Benjamin

et al. 2013

Blood

View full text Add to dashboard Cite

Key Points• RAS/MEK/ERK signaling is memory stage-dependent in human T cells, conferring susceptibility to alloreactive T-cell selective inhibition.• MEK inhibitors selectively inhibit alloreactive but not herpesvirus-specific human T cells and inhibit murine GVHD.Immunosuppressive strategies currently used in hematopoietic stem cell transplantation reliably decrease graft-versus-host disease (GVHD) rates, but also impair pathogenspecific immunity. Experimental transplant studies indicate that GVHD-initiating alloreactive T cells reside primarily in naive and central memory T-cell compartments. In contrast, virus-specific T cells comprise a more differentiated memory population. After finding that the rat sarcoma/mitogen-activated protein kinase kinase/extracellular receptor kinase (RAS/MEK/ERK) pathway is preferentially activated in naive and central memory human T cells, we hypothesized that MEK inhibitors would preferentially inhibit alloreactive T cells, while sparing more differentiated virus-specific T cells. Confirming our hypothesis, we found that MEK inhibitors including selumetinib preferentially inhibited cytokine production and alloreactivity mediated by naive and central memory human CD4 1 and CD8 1 T cells while sparing more differentiated T cells specific for the human herpesviruses cytomegalovirus and Epstein-Barr virus. We then demonstrated that short-term posttransplant administration of selumetinib in a major histocompatibility complex major-and minor-mismatched murine model significantly delayed the onset of GVHD-associated mortality without compromising myeloid engraftment, demonstrating the in vivo potential of MEK inhibitors in the setting of hematopoietic stem cell transplantation. These findings demonstrate that targeting memory-dependent differences in T-cell signaling is a potent and selective approach to inhibition of alloreactivity. (Blood. 2013;121(23):4617-4626)

show abstract

Cytokinetically quiescent (G0/G1) human multiple myeloma cells are susceptible to simultaneous inhibition of Chk1 and MEK1/2

Abstract: Effects of

Cited by 43 publications

References 48 publications

DNA repair of myeloma plasma cells correlates with clinical outcome: the effect of the nonhomologous end-joining inhibitor SCR7

DNA repair of myeloma plasma cells correlates with clinical outcome: the effect of the nonhomologous end-joining inhibitor SCR7

Enhancing CHK1 inhibitor lethality in glioblastoma

MEK inhibitors selectively suppress alloreactivity and graft-versus-host disease in a memory stage-dependent manner

Contact Info

Product

Resources

About