Werner Helicase Is a Synthetic-Lethal Vulnerability in Mismatch Repair–Deficient Colorectal Cancer Refractory to Targeted Therapies, Chemotherapy, and Immunotherapy

Abstract

Targeted therapies, chemotherapy, and immunotherapy are used to treat patients with mismatch repair-deficient (dMMR)/microsatellite instability-high (MSI-H) colorectal cancer (CRC). The clinical effectiveness of targeted therapy and chemotherapy is limited by resistance and drug toxicities, and about half of immunotherapy patients are refractory to immune checkpoint inhibitors. Loss of Werner syndrome ATP-dependent helicase (WRN) is a synthetic-lethality in dMMR/MSI-H cells. To inform the development of WRN as a therapeutic target, we performed WRN knockout or knockdown in 60 heterogeneous dMMR CRC preclinical models, demonstrating that WRN dependency is an almost universal feature and a robust marker for patient selection. Furthermore, models of resistance to clinically relevant targeted therapy, chemotherapy, and immunotherapy retain WRN dependency.These data show the potential of therapeutically targeting WRN in dMMR/MSI-H CRC patients, and support WRN as a therapeutic option for patients with dMMR/MSI-H cancers refractory to current treatment strategies. SIGNIFICANCEWe found that a large, diverse set of dMMR/MSI-H CRC preclinical models, including models of treatment refractory disease, are WRN dependent. Our results support WRN as a promising synthetic-lethal target in dMMR/MSI-H CRC tumors as a monotherapy or in combination with targeted agents, chemotherapy or immunotherapy. INTRODUCTIONDNA mismatch repair (MMR) is an evolutionarily conserved process that recognizes and repairs spontaneously mis-incorporated bases during DNA replication. Microsatellite instability (MSI) is caused by impaired MMR and is a ubiquitous feature in cancer, observed in >20 different tumor types and frequently present in colon, ovarian, endometrial, and gastric cancer, with hundreds of thousands of MSI cancer diagnoses worldwide each year.Lynch syndrome is caused by inherited MMR defects (1). Approximately 10 -15% of sporadic CRC display dMMR/MSI, with important prognostic and therapeutic implications for patients (2).Research.

Targeting IL8 as a sequential therapy strategy to overcome chemotherapy resistance in advanced gastric cancer

“…Chemotherapy resistance has been recognized as a major problem in cancer therapy, reducing the cytotoxic activity of anticancer agents. In addition to drug resistance after repeated use, the obvious toxic effects of chemotherapy drugs limit their clinical application [ 44 ]. Hence, the efficacy and tolerance of targeted drugs need to be simultaneously considered when hunting for targets after chemotherapy resistance.…”

LY6G6D is Epigenetically Activated in Classical Colorectal Adenocarcinoma and Hyper-Methylated in Mucinous Subtypes Determining Resistance to FOLFOX Therapeutic Regimens.

“…Over the last years the progress in cancer immunology has radically changed therapeutic strategies for the treatment of many types of solid tumors including colorectal cancer. For now, it is well-documented that drugs named immune checkpoint inhibitors are effective in a small subset of mismatch repair de cient (MMRd) malignancies [3,4,28]. Mismatch repair stable cancers represent the vast majority of CRCs and exhibit primary resistance to immune checkpoint inhibitors.…”

“…The international CRC subtyping consortium has de ned four molecular subtypes of CRC: consensus molecular subtypes (CMS)1 to CMS4, each of which has a characteristic molecular background characterized by a distinct gene expression, mutational status and in ammatory microenvironment [3]. However, this strati cation is not unambiguous, since also de ned subtypes often displaying intratumoral heterogeneity, whereby several subpopulations within one tumor show differences in in ammatory in ltrate, mutations and morphology [3,4]. These studies thus revealed that CRC is not one disease, but rather a collection of neoplastic diseases.…”

Recent Advances in the Development of Non-PIKKs Targeting Small Molecule Inhibitors of DNA Double-Strand Break Repair

“…The same group recently identified several non-specific reversible and irreversible helicase inhibitors through HTS using a larger library of approximately 350,000 small molecules ( 222 ). Several studies identified WRN synthetic lethal vulnerability in cancers with microsatellite instability ( 218 , 223 , 224 ), suggesting specific WRN inhibitors hold great potential to target microsatellite instability tumors to enable a clear stratification path in the clinic.…”