Cancer Medicine (Jan 2024)

Analysis of translesion polymerases in colorectal cancer cells following cetuximab treatment: A network perspective

  • Anubrata Das,
  • Georgios V. Gkoutos,
  • Animesh Acharjee

DOI
https://doi.org/10.1002/cam4.6945
Journal volume & issue
Vol. 13, no. 1
pp. n/a – n/a

Abstract

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Abstract Introduction Adaptive mutagenesis observed in colorectal cancer (CRC) cells upon exposure to EGFR inhibitors contributes to the development of resistance and recurrence. Multiple investigations have indicated a parallel between cancer cells and bacteria in terms of exhibiting adaptive mutagenesis. This phenomenon entails a transient and coordinated escalation of error‐prone translesion synthesis polymerases (TLS polymerases), resulting in mutagenesis of a magnitude sufficient to drive the selection of resistant phenotypes. Methods In this study, we conducted a comprehensive pan‐transcriptome analysis of the regulatory framework within CRC cells, with the objective of identifying potential transcriptome modules encompassing certain translesion polymerases and the associated transcription factors (TFs) that govern them. Our sampling strategy involved the collection of transcriptomic data from tumors treated with cetuximab, an EGFR inhibitor, untreated CRC tumors, and colorectal‐derived cell lines, resulting in a diverse dataset. Subsequently, we identified co‐regulated modules using weighted correlation network analysis with a minKMEtostay threshold set at 0.5 to minimize false‐positive module identifications and mapped the modules to STRING annotations. Furthermore, we explored the putative TFs influencing these modules using KBoost, a kernel PCA regression model. Results Our analysis did not reveal a distinct transcriptional profile specific to cetuximab treatment. Moreover, we elucidated co‐expression modules housing genes, for example, POLK, POLI, POLQ, REV1, POLN, and POLM. Specifically, POLK, POLI, and POLQ were assigned to the “blue” module, which also encompassed critical DNA damage response enzymes, for example. BRCA1, BRCA2, MSH6, and MSH2. To delineate the transcriptional control of this module, we investigated associated TFs, highlighting the roles of prominent cancer‐associated TFs, such as CENPA, HNF1A, and E2F7. Conclusion We found that translesion polymerases are co‐regulated with DNA mismatch repair and cell cycle‐associated factors. We did not, however, identified any networks specific to cetuximab treatment indicating that the response to EGFR inhibitors relates to a general stress response mechanism.

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