Replication Stress Defines Distinct Molecular Subtypes Across Cancers

Abstract

Endogenous replication stress is a major driver of genomic instability. Current assessments of replication stress are low throughput precluding its comprehensive assessment across tumors. Here we develop and validate a transcriptional profile of replication stress by leveraging established cellular characteristics that portend replication stress. The repstress gene signature defines a subset of tumors across lineages characterized by activated oncogenes, aneuploidy, extrachromosomal DNA amplification, immune evasion, high genomic instability, and poor survival, and importantly predicts response to agents targeting replication stress more robustly than previously reported transcriptomic measures of replication stress. Repstress score profiles the dual roles of replication stress during tumorigenesis and in established cancers and defines distinct molecular subtypes within cancers that may be more vulnerable to drugs targeting this dependency. Altogether, our study provides a molecular profile of replication stress, providing novel biological insights of the replication stress phenotype, with clinical implications.

ecDNA amplification ofMYCdrives intratumor copy-number heterogeneity and adaptation to stress in PDAC

“…ecDNA+ PDOs were also enriched for copy number signatures defining patterns of mid-level amplifications which have been associated with replication stress (CX9, Figure 1f ) 26 . Endogenous replication stress can cause genomic instability which in turn may result in ecDNA formation 27 . Consistent with this idea, ecDNA+ PDOs showed enrichment for a transcriptomic signature (CIN70) of chromosomal instability 28 ( Figure 1g ) .…”

Berzosertib Plus Topotecan vs Topotecan Alone in Patients With Relapsed Small Cell Lung Cancer

“…Genomic instability is an enabling characteristic of cancer, which by generating genetic diversity expedites the acquisition of multiple other hallmark capabilities . Replication stress, defined as the slowing or stalling of replication fork progression and DNA synthesis is a major driver of genomic instability . We reasoned that SCLC, being a smoking-related cancer, which is marked by extensive chromosomal rearrangements and high mutation rate, frequent inactivation of tumor suppressor genes TP53 and RB1 , extra-chromosomal amplification of MYC genes, and hyper-transcription, depends on an effective cellular response to replication stress to sustain its rapid proliferation .…”

“…9 Replication stress, defined as the slowing or stalling of replication fork progression and DNA synthesis is a major driver of genomic instability. 10 We reasoned that SCLC, being a smokingrelated cancer, which is marked by extensive chromosomal rearrangements and high mutation rate, frequent inactivation of tumor suppressor genes TP53 and RB1, 11 extra-chromosomal amplification of MYC genes, 12 and hyper-transcription, depends on an effective cellular response to replication stress to sustain its rapid proliferation. 13 Ataxia telangiectasia and Rad3-related (ATR) is a master regulator of the replication stress response, stabilizing the genome when DNA replication is compromised.…”

“…14 Enhancing replication stress in tumors that are already under high replication stress through ATR inhibition can induce cell death by mitotic catastrophe. 10,15 In a phase 1 clinical trial, we combined the first-in-class ATR inhibitor berzosertib with topotecan, which produces replication stress by trapping topoisomerase I (TOP1) cleavage complexes. 10,16 The combination enhanced replication stress and produced durable responses in patients with chemotherapy refractory cancers while being tolerable.…”

“…10,15 In a phase 1 clinical trial, we combined the first-in-class ATR inhibitor berzosertib with topotecan, which produces replication stress by trapping topoisomerase I (TOP1) cleavage complexes. 10,16 The combination enhanced replication stress and produced durable responses in patients with chemotherapy refractory cancers while being tolerable. 16 In a singlearm phase 2 trial, the combination yielded partial responses in 36% of patients with relapsed SCLC, meeting the primary objective.…”