CHFR silencing or microsatellite instability is associated with increased antitumor activity of docetaxel or gemcitabine in colorectal cancer

Abstract

Phenotypic differences among cancers with the same origin may be associated with chemotherapy response. CHFR silencing associated with DNA methylation has been suggested to be predictive of taxane sensitivity in diverse tumor types. However, the use of microsatellite instability (MSI:unstable--MSS:stable) as a predictive marker for therapeutic effect has had conflicting results. We examined these molecular alterations as predictors of chemotherapy sensitivity in colorectal cancer (CRC). Differential sensitivity to docetaxel and gemcitabine was compared to potential predictive biomarkers CHFR methylation and MSI status. Cell lines that were MSI-H/CHFR-methylated, MSS/CHFR-methylated, and MSS/CHFR-unmethylated were assessed for in vivo sensitivity of CRC cell line xenografts to docetaxel and/or gemcitabine. We observed increased sensitivity in vitro to gemcitabine in cell lines with MSI and docetaxel in cell lines with CHFR inactivation via DNA methylation. In vivo treatment of human xenografts confirmed differential sensitivity, with the MSI-H/CHFR-methylated line RKO having tumor growth inhibition to each agent, and at least additive tumor growth inhibition with combination therapy. The MSS-CHFR-unmethylated line, CACO2, was resistant to single and combination therapy, while COLO205, the MSS/CHFR-methylated line, showed tumor growth inhibition with docetaxel, but not gemcitabine, therapy. CHFR methylation in CRC cell lines predicted for sensitivity in vitro and in vivo to docetaxel, while MSI-H cell lines were more sensitive to gemcitabine. These data suggest that a subset of CRC patients would be selectively sensitive to a novel combination of gemcitabine and docetaxel, and are the basis for an ongoing clinical trial of this combination in a biomarker-selected patient population.

Small molecule inhibition of the CHFR-PARP1 interaction as novel approach to overcome intrinsic taxane resistance in cancer

“…We furthermore show that this interaction is mediated by CHFR's PBZ domain and that its disruption either by mutation of the PBZ domain or PARP1 knockdown leads to auto-ubiquitination and subsequent proteasomal degradation of CHFR. Together with previously published results that reduced CHFR expression in lung cancer is associated with improved survival following platinum taxane based therapy [ 6 ] and that taxane sensitivity is increased in gastric [ 1 ]-, colon [ 2 ]- and cervical cancers [ 22 ] in which CHFR is silenced epigenetically, we proposed a model in which pharmacologic inhibition of the CHFR-PARP1 interaction with subsequent loss of CHFR and disruption of antephase checkpoint function helps to overcome intrinsic taxane resistance across a wide spectrum of different tumor types (Figure 7 ).…”

“…Unfortunately, primary resistance to taxanes is common and poses an important clinical problem. The mitotic checkpoint gene “checkpoint with forkhead and ringfinger domains” (CHFR) has recently emerged as a critical mediator of resistance against microtubular-targeted therapies in various different cancer types including gastric-[ 1 ], colon-[ 2 , 3 ], endometrial-,[ 4 , 5 ] and lung cancer [ 6 ]. Epigenetic silencing of CHFR by promoter hypermethylation or reduced protein expression have been described as predictive biomarkers for taxane sensitivity.…”

Chemo-immunotherapy improves long-term survival in a preclinical model of MMR-D-related cancer

“…Besides, we and others were able to show that GEM exerts direct toxic effects towards MMR-D tumor cells of different origin (i.e. solid tumor vs. hematological malignancies) [27, 28]. Inhibition of cell proliferation was achieved at concentrations well below plasma levels under standard therapy [27] and accompanied by classical signs of ICD induction (exposure of CalR, HMGB1 release), the latter shown here on three low-passage murine MMR-D cell lines.…”

Epigenetic Modifications as Biomarkers of Tumor Development, Therapy Response, and Recurrence across the Cancer Care Continuum

“…Hypermethylation of CHFR is observed in breast, bladder, colorectal, gastric, nasopharyngeal, lung, esophageal, cervical, hepatocellular, oral squamous, head and neck, and endometrial cancer [ 152 ]; and is a potential marker of taxane sensitivity for many cancer types. In vitro evidence using nasopharyngeal carcinoma, colorectal cancer, esophageal, endometrial cancer, and gastric cancer cell lines suggests that CHFR hypermethylation contributes to docetaxel and paclitaxel sensitivity [ 153 , 154 , 155 , 156 , 157 ]. However, subsequent clinical studies have not shown a clear influence of CHFR methylation on taxane sensitivity.…”