Phosphoproteomics of patient-derived xenografts identifies targets and markers associated with sensitivity and resistance to EGFR blockade in colorectal cancer.

Autor:	Beekhof R; Amsterdam UMC, Vrije Universiteit Amsterdam, Medical Oncology, Cancer Center Amsterdam, De Boelelaan 1117, 1081 HV Amsterdam, Netherlands.; Amsterdam UMC, Vrije Universiteit Amsterdam, OncoProteomics Laboratory, Cancer Center Amsterdam, De Boelelaan 1117, 1081 HV Amsterdam, Netherlands., Bertotti A; Candiolo Cancer Institute - FPO IRCCS, Candiolo, 10060 Torino, Italy.; Department of Oncology, University of Torino, Candiolo, 10060 Torino, Italy., Böttger F; Amsterdam UMC, Vrije Universiteit Amsterdam, Medical Oncology, Cancer Center Amsterdam, De Boelelaan 1117, 1081 HV Amsterdam, Netherlands.; Amsterdam UMC, Vrije Universiteit Amsterdam, OncoProteomics Laboratory, Cancer Center Amsterdam, De Boelelaan 1117, 1081 HV Amsterdam, Netherlands.; Division of Molecular Carcinogenesis, Netherlands Cancer Institute, Oncode Institute, 1066 CX Amsterdam, Netherlands., Vurchio V; Candiolo Cancer Institute - FPO IRCCS, Candiolo, 10060 Torino, Italy.; Department of Oncology, University of Torino, Candiolo, 10060 Torino, Italy., Cottino F; Candiolo Cancer Institute - FPO IRCCS, Candiolo, 10060 Torino, Italy., Zanella ER; Candiolo Cancer Institute - FPO IRCCS, Candiolo, 10060 Torino, Italy., Migliardi G; Candiolo Cancer Institute - FPO IRCCS, Candiolo, 10060 Torino, Italy.; Department of Oncology, University of Torino, Candiolo, 10060 Torino, Italy., Viviani M; Candiolo Cancer Institute - FPO IRCCS, Candiolo, 10060 Torino, Italy.; Department of Oncology, University of Torino, Candiolo, 10060 Torino, Italy., Grassi E; Candiolo Cancer Institute - FPO IRCCS, Candiolo, 10060 Torino, Italy.; Department of Oncology, University of Torino, Candiolo, 10060 Torino, Italy., Lupo B; Candiolo Cancer Institute - FPO IRCCS, Candiolo, 10060 Torino, Italy., Henneman AA; Amsterdam UMC, Vrije Universiteit Amsterdam, Medical Oncology, Cancer Center Amsterdam, De Boelelaan 1117, 1081 HV Amsterdam, Netherlands.; Amsterdam UMC, Vrije Universiteit Amsterdam, OncoProteomics Laboratory, Cancer Center Amsterdam, De Boelelaan 1117, 1081 HV Amsterdam, Netherlands., Knol JC; Amsterdam UMC, Vrije Universiteit Amsterdam, Medical Oncology, Cancer Center Amsterdam, De Boelelaan 1117, 1081 HV Amsterdam, Netherlands.; Amsterdam UMC, Vrije Universiteit Amsterdam, OncoProteomics Laboratory, Cancer Center Amsterdam, De Boelelaan 1117, 1081 HV Amsterdam, Netherlands., Pham TV; Amsterdam UMC, Vrije Universiteit Amsterdam, Medical Oncology, Cancer Center Amsterdam, De Boelelaan 1117, 1081 HV Amsterdam, Netherlands.; Amsterdam UMC, Vrije Universiteit Amsterdam, OncoProteomics Laboratory, Cancer Center Amsterdam, De Boelelaan 1117, 1081 HV Amsterdam, Netherlands., de Goeij-de Haas R; Amsterdam UMC, Vrije Universiteit Amsterdam, Medical Oncology, Cancer Center Amsterdam, De Boelelaan 1117, 1081 HV Amsterdam, Netherlands.; Amsterdam UMC, Vrije Universiteit Amsterdam, OncoProteomics Laboratory, Cancer Center Amsterdam, De Boelelaan 1117, 1081 HV Amsterdam, Netherlands., Piersma SR; Amsterdam UMC, Vrije Universiteit Amsterdam, Medical Oncology, Cancer Center Amsterdam, De Boelelaan 1117, 1081 HV Amsterdam, Netherlands.; Amsterdam UMC, Vrije Universiteit Amsterdam, OncoProteomics Laboratory, Cancer Center Amsterdam, De Boelelaan 1117, 1081 HV Amsterdam, Netherlands., Labots M; Amsterdam UMC, Vrije Universiteit Amsterdam, Medical Oncology, Cancer Center Amsterdam, De Boelelaan 1117, 1081 HV Amsterdam, Netherlands., Verheul HMW; Amsterdam UMC, Vrije Universiteit Amsterdam, Medical Oncology, Cancer Center Amsterdam, De Boelelaan 1117, 1081 HV Amsterdam, Netherlands.; Department of Medical Oncology, Erasmus MC Cancer Institute, Erasmus University Medical Center Rotterdam, Dr. Molewaterplein 40, 3015 GD Rotterdam, Netherlands., Trusolino L; Candiolo Cancer Institute - FPO IRCCS, Candiolo, 10060 Torino, Italy.; Department of Oncology, University of Torino, Candiolo, 10060 Torino, Italy., Jimenez CR; Amsterdam UMC, Vrije Universiteit Amsterdam, Medical Oncology, Cancer Center Amsterdam, De Boelelaan 1117, 1081 HV Amsterdam, Netherlands.; Amsterdam UMC, Vrije Universiteit Amsterdam, OncoProteomics Laboratory, Cancer Center Amsterdam, De Boelelaan 1117, 1081 HV Amsterdam, Netherlands.
Jazyk:	angličtina
Zdroj:	Science translational medicine [Sci Transl Med] 2023 Aug 16; Vol. 15 (709), pp. eabm3687. Date of Electronic Publication: 2023 Aug 16.
DOI:	10.1126/scitranslmed.abm3687
Abstrakt:	Epidermal growth factor receptor (EGFR) is a well-exploited therapeutic target in metastatic colorectal cancer (mCRC). Unfortunately, not all patients benefit from current EGFR inhibitors. Mass spectrometry-based proteomics and phosphoproteomics were performed on 30 genomically and pharmacologically characterized mCRC patient-derived xenografts (PDXs) to investigate the molecular basis of response to EGFR blockade and identify alternative drug targets to overcome resistance. Both the tyrosine and global phosphoproteome as well as the proteome harbored distinctive response signatures. We found that increased pathway activity related to mitogen-activated protein kinase (MAPK) inhibition and abundant tyrosine phosphorylation of cell junction proteins, such as CXADR and CLDN1/3, in sensitive tumors, whereas epithelial-mesenchymal transition and increased MAPK and AKT signaling were more prevalent in resistant tumors. Furthermore, the ranking of kinase activities in single samples confirmed the driver activity of ERBB2, EGFR, and MET in cetuximab-resistant tumors. This analysis also revealed high kinase activity of several members of the Src and ephrin kinase family in 2 CRC PDX models with genomically unexplained resistance. Inhibition of these hyperactive kinases, alone or in combination with cetuximab, resulted in growth inhibition of ex vivo PDX-derived organoids and in vivo PDXs. Together, these findings highlight the potential value of phosphoproteomics to improve our understanding of anti-EGFR treatment and response prediction in mCRC and bring to the forefront alternative drug targets in cetuximab-resistant tumors.
Databáze:	MEDLINE
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