Trends in Cancer

Volume 6, Issue 12, December 2020, Pages 989-1001

Review

TRAIL of Hope Meeting Resistance in Cancer

David Deng 1 2, Khalid Shah 1 2 3

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Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) induces apoptosis

selectively via its interaction with the death receptors TRAILR1/DR4 and TRAILR2/DR5 in
a wide range of cancers, while sparing normal cells. Despite its tremendous potential for
cancer therapeutics, the translation of TRAIL into the clinic has been confounded by
TRAIL-resistant cancer populations. We discuss different molecular mechanisms
underlying TRAIL-mediated apoptosis and resistance to TRAIL. We also discuss the
successes and failures of recent preclinical and clinical studies of TRAIL-induced
apoptosis, and current attempts to overcome TRAIL resistance, and we provide a
perspective for improving the prospects of future clinical implementation.

Section snippets

TRAIL Resistance

Although TRAIL has demonstrated tremendous promise in preclinical studies, both in

vitro and in vivo studies have shown that, although most cancer cell lines display some
degree of sensitivity to TRAIL-mediated killing, a proportion harbor innate resistance.
Furthermore, as the tumor genome evolves under the selective pressure, many tumors
can also later acquire TRAIL resistance and relapse. Multiple studies have demonstrated
that resistance to TRAIL-mediated apoptosis is diverse and can occur…

Overcoming TRAIL Resistance

Given the increasing number of resistance mechanisms that have been discovered,
different strategies have been implemented to overcome various types of TRAIL
resistance. One of the most common strategies is to combine different therapeutic
modes. Targeting multiple pathways decreases the likelihood of two simultaneous
mutations arising in the same clone, and functional redundancy and compensation
between pathways also rationalize combination therapy. We summarize some promising
preclinical…

Clinical Trials

Despite the rapid development of creative and novel approaches to overcome TRAIL
resistance, few preclinical studies have progressed to clinical trials. In previous clinical
trials TRAIL-based therapeutics have largely failed to synergize with other existing
chemotherapies or extend cancer patient survival significantly. We summarize some
recent and ongoing oncology clinical trials utilizing the principles of TRAIL-induced
apoptosis in Table 2.

The main challenges for TRAIL therapy in the clinic …

Concluding Remarks

TRAIL represents one of the most promising approaches to treat cancer owing to its
specificity, safety, and encouraging results in vitro. However, its complex interactions
with other pathways in a diverse, cell-dependent manner and widespread resistance
pose significant hurdles for the clinical development of TRAIL-based therapeutics.
Nonetheless, attempts to understand and circumvent the resistance mechanisms remain
enthusiastic in both clinical and preclinical studies (see Outstanding…

Acknowledgments

This work was supported by National Institutes of Health grants R01-CA201148 and
Department of Defense grant LC180495 to K.S.…

Disclaimer Statement
K.S. owns equity in and is a member of the Board of Directors of AMASA Therapeutics, a
company developing stem cell-based therapies for cancer. His interests were reviewed
and are managed by Brigham and Women’s Hospital and Partners HealthCare in
accordance with their conflict of interest policies. The other authors declare that they
have no competing interests.…

Glossary

Apoptosis
a type of programmed cell death that can be activated via two pathways: the
extrinsic apoptosis pathway and the intrinsic apoptosis pathway. The former is
mediated by TNF receptor superfamily that includes the canonical death
receptors, and the latter involves mitochondrial proteins and p53 activation.
Although the two pathways act independently, there is major crosstalk between
the pathways in mediating apoptosis and TRAIL resistance.

Caspases
a family of cysteine-aspartic proteases

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