Universität zu Köln

von Karstedt, Silvia ORCID: 0000-0002-7816-5919 and Walczak, Henning ORCID: 0000-0002-6312-4591 (2020). An unexpected turn of fortune: targeting TRAIL-Rs in KRAS-driven cancer. Cell Death Discov., 6 (1). LONDON: NATURE PUBLISHING GROUP. ISSN 2058-7716

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Abstract

Twenty-one percent of all human cancers bear constitutively activating mutations in the proto-oncogene KRAS. This incidence is substantially higher in some of the most inherently therapy-resistant cancers including 30% of non-small cell lung cancers (NSCLC), 50% of colorectal cancers, and 95% of pancreatic ductal adenocarcinomas (PDAC). Importantly, survival of patients with KRAS-mutated PDAC and NSCLC has not significantly improved since the 1970s highlighting an urgent need to re-examine how oncogenic KRAS influences cell death signaling outputs. Interestingly, cancers expressing oncogenic KRAS manage to escape antitumor immunity via upregulation of programmed cell death 1 ligand 1 (PD-L1). Recently, the development of next-generation KRAS(G12C)-selective inhibitors has shown therapeutic efficacy by triggering antitumor immunity. Yet, clinical trials testing immune checkpoint blockade in KRAS-mutated cancers have yielded disappointing results suggesting other, additional means endow these tumors with the capacity to escape immune recognition. Intriguingly, oncogenic KRAS reprograms regulated cell death pathways triggered by death receptors of the tumor necrosis factor (TNF) receptor superfamily. Perverting the course of their intended function, KRAS-mutated cancers use endogenous TNF-related apoptosis-inducing ligand (TRAIL) and its receptor(s) to promote tumor growth and metastases. Yet, endogenous TRAIL-TRAIL-receptor signaling can be therapeutically targeted and, excitingly, this may not only counteract oncogenic KRAS-driven cancer cell migration, invasion, and metastasis, but also the immunosuppressive reprogramming of the tumor microenvironment it causes. Here, we provide a concise summary of the current literature on oncogenic KRAS-mediated reprogramming of cell death signaling and antitumor immunity with the aim to open novel perspectives on combinatorial treatment strategies involving death receptor targeting.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code von Karstedt, Silvia UNSPECIFIED orcid.org/0000-0002-7816-5919 UNSPECIFIED Walczak, Henning UNSPECIFIED orcid.org/0000-0002-6312-4591 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-340714
DOI:	10.1038/s41420-020-0249-4
Journal or Publication Title:	Cell Death Discov.
Volume:	6
Number:	1
Date:	2020
Publisher:	NATURE PUBLISHING GROUP
Place of Publication:	LONDON
ISSN:	2058-7716
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language LIGAND TRAIL; CTLA-4 BLOCKADE; APOPTOSIS; DEATH; RAS; ACTIVATION; PROMOTES; CELLS; RESISTANCE; INHIBITORS Multiple languages Cell Biology Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/34071