Overcoming Cancer Cell Resistance to Death Receptor Targeted Therapies

Twomey, Julianne D.; Hallett, William; Zhang, Baolin

doi:10.1007/978-3-319-17807-3_10

Cited by 1 publication

(2 citation statements)

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“…A body of preclinical evidence showed that recombinant human TRAIL preferentially induced apoptosis in cancer cells without harming most normal cells [ 2 , 3 ]. This unique selectivity led to multiple clinical programs aimed at evaluating the antitumor activities of recombinant human TRAIL and agonistic antibodies against DR4 or DR5 [ 4 ]. These agents were shown to have a well-tolerated safety profile in early phases of clinical studies.…”

Section: Introductionmentioning

confidence: 99%

“…These agents were shown to have a well-tolerated safety profile in early phases of clinical studies. Unfortunately, their therapeutic effects were limited partly due to tumor resistance arising from various mechanisms such as lack of caspase-8 and caspase-10 expression and upregulation of anti-apoptosis proteins such as c-FLIP, XIAP, and Bcl-2 family member proteins [ 4 ]. Recent efforts were shifted to the development of second generation DR5-targeted agents with expected improvement in therapeutic effects [ 5 , 6 ].…”

Section: Introductionmentioning

confidence: 99%

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Cytokeratin 8/18 protects breast cancer cell lines from TRAIL-induced apoptosis

Bozza

Zhang

2018

Oncotarget

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TNF-related apoptosis inducing ligand (TRAIL) induces apoptosis by engaging its death receptors (DRs) 4 and/or 5 on targeted cells. Clinical attempts to stimulate this apoptotic pathway for cancer therapy, including the use of recombinant human TRAIL (rhTRAIL) or receptor agonistic antibodies, have been underway for over a decade. Unfortunately, these agents have only shown limited therapeutic effects due largely to tumor resistance arising from mechanisms yet to be defined. Here we show that intermediate filament proteins, keratin 8 and keratin 18 (K8/K18), negatively regulate TRAIL induced apoptosis. K8/K18 protein levels are consistently higher in TRAIL-resistant cells compared to TRAIL-sensitive cells in a panel of breast cancer cell lines. Blockade of K8 increased expression of DR5 on the surface of targeted cells and sensitized the cells to TRAIL-induced apoptosis. Conversely, ectopic expression of K8/K18 downregulated DR5 protein expression. K8/K18 appears to negatively regulate apoptosis signaling via DR5 in breast cancer cells. Our findings warrant additional studies to determine if K8/K18 could be a predictor of tumor resistance to DR5-targeted therapies.

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Section: Introductionmentioning

confidence: 99%