Polo-like kinase 1 inhibitors in refractory colorectal cancer: deciphering the myth of synthetic lethality

Metastatic colorectal cancer (mCRC) remains a highly lethal disease because resistance to chemotherapy and targeted agents—including anti-VEGF and anti-EGFR therapies—emerges rapidly and universally. In RAS‑mutant mCRC, second-line treatment with FOLFIRI plus bevacizumab achieves modest clinical ben...

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Autores: Rojas, Mariam, Gonzalez, Laura, Cascante i Serratosa, Marta, Maurel Santasusana, Joan
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2024
País:España
Institución:Universidad de Barcelona
Repositorio:Dipòsit Digital de la UB
OAI Identifier:oai:diposit.ub.edu:2445/226564
Acceso en línea:https://hdl.handle.net/2445/226564
Access Level:acceso abierto
Palabra clave:Càncer colorectal
Quimioteràpia del càncer
Colorectal cancer
Cancer chemotherapy
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spelling Polo-like kinase 1 inhibitors in refractory colorectal cancer: deciphering the myth of synthetic lethalityRojas, MariamGonzalez, LauraCascante i Serratosa, MartaMaurel Santasusana, JoanCàncer colorectalQuimioteràpia del càncerColorectal cancerCancer chemotherapyMetastatic colorectal cancer (mCRC) remains a highly lethal disease because resistance to chemotherapy and targeted agents—including anti-VEGF and anti-EGFR therapies—emerges rapidly and universally. In RAS‑mutant mCRC, second-line treatment with FOLFIRI plus bevacizumab achieves modest clinical benefit, underscoring the need to understand mechanisms of resistance and develop rational combination strategies. Recent evidence implicates oxidative phosphorylation (OXPHOS), antioxidant programs such as the pentose phosphate pathway (PPP), and polo-like kinase 1 (PLK1)–dependent cell‑cycle regulation as key determinants of therapeutic refractoriness. In a recent phase Ib study, onvansertib, a PLK1 inhibitor, combined with FOLFIRI and bevacizumab produced a notable 44% response rate and a median progression-free survival of 12.6 months in RAS‑mutant tumors, suggesting a subset of patients may derive meaningful benefit. Integrating these clinical findings with current metabolic and genomic insights, we highlight how OXPHOS‑driven tumors activate antioxidant networks, sustain chromosome instability, and remodel nutrient usage—features that may blunt synthetic lethality and foster resistance to DNA‑damaging agents, PARP inhibitors, and PLK1 inhibition. We also discuss how altered DNA‑repair reliance (HR, NHEJ, and MMEJ), lactate‑supported mitochondrial metabolism, ENPP1‑mediated immunosuppression, and MYC activation converge to shape chemoresistance and impaired immune responses in microsatellite‑stable colorectal cancer. A more precise therapeutic approach may require selecting patients with combined OXPHOS and PPP activation and leveraging rational combinations involving PLK1, PARP, or ENPP1 inhibitors together with immune checkpoint blockade. Such strategies could enhance the efficacy of ongoing clinical trials and refine future treatment paradigms for heavily pretreated colorectal cancer.AME Publishing Company2024info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfhttps://hdl.handle.net/2445/226564Articles publicats en revistes (Bioquímica i Biomedicina Molecular)reponame:Dipòsit Digital de la UBinstname:Universidad de BarcelonaInglésReproducció del document publicat a: https://doi.org/10.21037/actr-24-68AME Clinical Trials Review, 2024, vol. 2, p. 1-5https://doi.org/10.21037/actr-24-68cc-by-nc-nd (c) AME Publishing Company, 2024http://creativecommons.org/licenses/by-nc-nd/4.0/info:eu-repo/semantics/openAccessoai:diposit.ub.edu:2445/2265642026-05-27T06:46:51Z
dc.title.none.fl_str_mv Polo-like kinase 1 inhibitors in refractory colorectal cancer: deciphering the myth of synthetic lethality
title Polo-like kinase 1 inhibitors in refractory colorectal cancer: deciphering the myth of synthetic lethality
spellingShingle Polo-like kinase 1 inhibitors in refractory colorectal cancer: deciphering the myth of synthetic lethality
Rojas, Mariam
Càncer colorectal
Quimioteràpia del càncer
Colorectal cancer
Cancer chemotherapy
title_short Polo-like kinase 1 inhibitors in refractory colorectal cancer: deciphering the myth of synthetic lethality
title_full Polo-like kinase 1 inhibitors in refractory colorectal cancer: deciphering the myth of synthetic lethality
title_fullStr Polo-like kinase 1 inhibitors in refractory colorectal cancer: deciphering the myth of synthetic lethality
title_full_unstemmed Polo-like kinase 1 inhibitors in refractory colorectal cancer: deciphering the myth of synthetic lethality
title_sort Polo-like kinase 1 inhibitors in refractory colorectal cancer: deciphering the myth of synthetic lethality
dc.creator.none.fl_str_mv Rojas, Mariam
Gonzalez, Laura
Cascante i Serratosa, Marta
Maurel Santasusana, Joan
author Rojas, Mariam
author_facet Rojas, Mariam
Gonzalez, Laura
Cascante i Serratosa, Marta
Maurel Santasusana, Joan
author_role author
author2 Gonzalez, Laura
Cascante i Serratosa, Marta
Maurel Santasusana, Joan
author2_role author
author
author
dc.subject.none.fl_str_mv Càncer colorectal
Quimioteràpia del càncer
Colorectal cancer
Cancer chemotherapy
topic Càncer colorectal
Quimioteràpia del càncer
Colorectal cancer
Cancer chemotherapy
description Metastatic colorectal cancer (mCRC) remains a highly lethal disease because resistance to chemotherapy and targeted agents—including anti-VEGF and anti-EGFR therapies—emerges rapidly and universally. In RAS‑mutant mCRC, second-line treatment with FOLFIRI plus bevacizumab achieves modest clinical benefit, underscoring the need to understand mechanisms of resistance and develop rational combination strategies. Recent evidence implicates oxidative phosphorylation (OXPHOS), antioxidant programs such as the pentose phosphate pathway (PPP), and polo-like kinase 1 (PLK1)–dependent cell‑cycle regulation as key determinants of therapeutic refractoriness. In a recent phase Ib study, onvansertib, a PLK1 inhibitor, combined with FOLFIRI and bevacizumab produced a notable 44% response rate and a median progression-free survival of 12.6 months in RAS‑mutant tumors, suggesting a subset of patients may derive meaningful benefit. Integrating these clinical findings with current metabolic and genomic insights, we highlight how OXPHOS‑driven tumors activate antioxidant networks, sustain chromosome instability, and remodel nutrient usage—features that may blunt synthetic lethality and foster resistance to DNA‑damaging agents, PARP inhibitors, and PLK1 inhibition. We also discuss how altered DNA‑repair reliance (HR, NHEJ, and MMEJ), lactate‑supported mitochondrial metabolism, ENPP1‑mediated immunosuppression, and MYC activation converge to shape chemoresistance and impaired immune responses in microsatellite‑stable colorectal cancer. A more precise therapeutic approach may require selecting patients with combined OXPHOS and PPP activation and leveraging rational combinations involving PLK1, PARP, or ENPP1 inhibitors together with immune checkpoint blockade. Such strategies could enhance the efficacy of ongoing clinical trials and refine future treatment paradigms for heavily pretreated colorectal cancer.
publishDate 2024
dc.date.none.fl_str_mv 2024
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv https://hdl.handle.net/2445/226564
url https://hdl.handle.net/2445/226564
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Reproducció del document publicat a: https://doi.org/10.21037/actr-24-68
AME Clinical Trials Review, 2024, vol. 2, p. 1-5
https://doi.org/10.21037/actr-24-68
dc.rights.none.fl_str_mv cc-by-nc-nd (c) AME Publishing Company, 2024
http://creativecommons.org/licenses/by-nc-nd/4.0/
info:eu-repo/semantics/openAccess
rights_invalid_str_mv cc-by-nc-nd (c) AME Publishing Company, 2024
http://creativecommons.org/licenses/by-nc-nd/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv AME Publishing Company
publisher.none.fl_str_mv AME Publishing Company
dc.source.none.fl_str_mv Articles publicats en revistes (Bioquímica i Biomedicina Molecular)
reponame:Dipòsit Digital de la UB
instname:Universidad de Barcelona
instname_str Universidad de Barcelona
reponame_str Dipòsit Digital de la UB
collection Dipòsit Digital de la UB
repository.name.fl_str_mv
repository.mail.fl_str_mv
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