Improving the Efficacy of Chemoradiation with Targeted Agents

Morgan, Meredith A.; Parsels, Leslie A.; Maybaum, Jonathan; Lawrence, Theodore S.

doi:10.1158/2159-8290.cd-13-0337

Cited by 78 publications

(80 citation statements)

References 92 publications

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“…Cells were injected s.c. into the dorsal flanks of the mice at day 0 (2 Â 10 6 cells). Tumor size was measured by calipers and calculated by the formula of (p)/6 Â (large diameter) Â (small diameter) 2 . Following the establishment of tumors, mice were treated with single or fractionated doses of IgG, MEHD7945A, radiation or radiation in combination with MEHD7945A.…”

Section: Human Tumor Xenograftsmentioning

confidence: 99%

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Antitumor Effects of MEHD7945A, a Dual-Specific Antibody against EGFR and HER3, in Combination with Radiation in Lung and Head and Neck Cancers

Huang

Armstrong

et al. 2015

Molecular Cancer Therapeutics

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Human epidermal growth factor receptor family members (EGFR, HER2, HER3, and HER4) play important roles in tumorigenesis and response to cancer therapeutics. In this study, we evaluated the capacity of the dual-target antibody MEHD7945A that simultaneously targets EGFR and HER3 to modulate radiation response in lung and head and neck cancer models. Antitumor effects of MEHD7945A in combination with radiation were evaluated in cell culture and tumor xenograft models. Mechanisms that may contribute to increased radiation killing by MEHD7945A, including DNA damage and inhibition of EGFR-HER signaling pathways, were analyzed.

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Section: Human Tumor Xenograftsmentioning

confidence: 99%

“…However, normal tissue tolerance is often a limiting factor for high-dose radiation delivery in various anatomic sites. Combining radiation with cytotoxic chemotherapy or molecular-targeted therapies offers the potential to improve therapeutic outcome (1)(2)(3)(4).…”

Section: Introductionmentioning

confidence: 99%

Antitumor Effects of MEHD7945A, a Dual-Specific Antibody against EGFR and HER3, in Combination with Radiation in Lung and Head and Neck Cancers

Huang

Armstrong

et al. 2015

Molecular Cancer Therapeutics

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“…Among all chemotherapy agents, the greatest potentiation by CHK1 inhibitors has been reported with antimetabolites, notably gemcitabine (10). Gemcitabine is standard for patients with pancreatic ductal adenocarcinoma, one of the most intractable of human malignancies (11).…”

Section: Introductionmentioning

confidence: 99%

CHK1 Inhibition Synergizes with Gemcitabine Initially by Destabilizing the DNA Replication Apparatus

et al. 2015

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Combining cell-cycle checkpoint kinase inhibitors with the DNA-damaging chemotherapeutic agent gemcitabine offers clinical appeal, with a mechanistic rationale based chiefly on abrogation of gemcitabine-induced G 2 -M checkpoint activation. However, evidence supporting this mechanistic rationale from chemosensitization studies has not been consistent. Here we report a systematic definition of how pancreatic cancer cells harboring mutant p53 respond to this combination therapy, by combining mathematical models with large-scale quantitative biologic analyses of single cells and cell populations. Notably, we uncovered a dynamic range of mechanistic effects at different ratios of gemcitabine and CHK1 inhibitors. Remarkably, effective synergy was attained even where cells exhibited an apparently functional G 2 -M surveillance mechanism, as exemplified by a lack of both overt premature CDK1 activation and S-phase mitotic entry. Consistent with these findings, S-G 2 duration was extended in treated cells, leading to a definable set of lineage-dependent catastrophic fates. At synergistic drug concentrations, global replication stress was a distinct indicator of chemosensitization as characterized molecularly by an accumulation of S-phase cells with high levels of hyperphosphorylated RPA-loaded single-stranded DNA. In a fraction of these cells, persistent genomic damage was observed, including chromosomal fragmentation with a loss of centromeric regions that prevented proper kinetochore-microtubule attachment. Together, our results suggested a "foot-in-the-door" mechanism for drug synergy where cells were destroyed not by frank G 2 -M phase abrogation but rather by initiating a cumulative genotoxicity that deregulated DNA synthesis. Cancer Res; 75(17); 3583-95. Ó2015 AACR.

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“…Here the anticipated effect of Wee1 inhibition would be to abrogate the G2 checkpoint, resulting in cells entering mitosis with unresolved radiation-induced chromosomal damage, and thereby undergoing death through mitotic catastrophe. 12,23,24 Pancreatic cancers are characterized by their poor response to both chemotherapy and radiotherapy. Preclinical studies suggest that MK-1775 might be combined effectively with either of these treatment modalities, and improve the outcome for pancreatic cancer patients.…”

Section: Introductionmentioning

confidence: 99%

Cytokinetic effects of Wee1 disruption in pancreatic cancer

et al. 2016

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The Wee1 kinase, which is activated in response to DNA damage, regulates exit from G2 through inhibitory phosphorylation of Cdk1/Cdc2, and is an attractive drug target. However, recent work has highlighted effects of Cdk2 phosphorylation by Wee1 on movement through S-phase, suggesting the potential to sensitize to S-phase specific agents by Wee1 inhibitors. In this paper we applied multiparametric flow cytometry to patient-derived pancreatic cancer xenograft tumor cells to study the cell cycle perturbations of Wee1 disruption via the small molecule inhibitor MK-1775, and genetic knockdown. We find that in vitro treatment with MK-1775, and to a lesser degree, Wee1 RNA transcript knockdown, results in the striking appearance of S-phase cells prematurely entering into mitosis. This effect was not seen in vivo in any of the models tested. Here, although we noted an increase of S-phase cells expressing the damage response marker gH2AX, treatment with MK-1775 did not significantly sensitize cells to the cytidine analog gemcitabine. Treatment with MK-1775 did result in a transient but large increase in cells expressing the mitotic marker phosphorylated H3S10 that reached a peak 4 hours after treatment. This suggests a role for Wee1 regulating the progression of genomically unstable cancer cells through G2 in the absence of extrinsically-applied DNA damage. A single dose of 8Gy ionizing radiation resulted in the time-dependent accumulation of Cyclin A2 positive/phosphorylated H3S10 negative cells at the 4N position, which was abrogated by treatment with MK-1775. Consistent with these findings, a genomescale pooled RNA interference screen revealed that toxic doses of MK-1775 are suppressed by CDK2 or Cyclin A2 knockdown. These findings support G2 exit as the more significant effect of Wee1 inhibition in pancreatic cancers.

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Improving the Efficacy of Chemoradiation with Targeted Agents

Cited by 78 publications

References 92 publications

Antitumor Effects of MEHD7945A, a Dual-Specific Antibody against EGFR and HER3, in Combination with Radiation in Lung and Head and Neck Cancers

Antitumor Effects of MEHD7945A, a Dual-Specific Antibody against EGFR and HER3, in Combination with Radiation in Lung and Head and Neck Cancers

CHK1 Inhibition Synergizes with Gemcitabine Initially by Destabilizing the DNA Replication Apparatus

Cytokinetic effects of Wee1 disruption in pancreatic cancer

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