Activation of the IFN signaling pathway is associated with resistance to CDK4/6 inhibitors and immune checkpoint activation in ER-positive breast cancer Journal Article

   

Authors:	De Angelis, C.; Fu, X. Y.; Cataldo, M. L.; Nardone, A.; Pereira, R.; Veeraraghavan, J.; Nanda, S.; Qin, L. F.; Sethunath, V.; Wang, T.; Hilsenbeck, S. G.; Benelli, M.; Migliaccio, I.; Guarducci, C.; Malorni, L.; Litchfield, L. M.; Liu, J. G.; Donaldson, J.; Selenica, P.; Brown, D. N.; Weigelt, B.; Reis-Filho, J. S.; Park, B.; Hurvitz, S. A.; Slamon, D. J.; Rimawi, M. F.; Jansen, V. M.; Jeselsohn, R.; Osborne, C. K.; Schiff, R.
Article Title:	Activation of the IFN signaling pathway is associated with resistance to CDK4/6 inhibitors and immune checkpoint activation in ER-positive breast cancer
Abstract:	Purpose: Cydin-dependent kinase 4 (CDK4) and CDK6 inhibitors (CDK4/60 are highly effective against estrogen receptor-positive (ER+)/HER2(-) breast cancer; however, intrinsic and acquired resistance is common. Elucidating the molecular features of sensitivity and resistance to CDK4/6i may lead to identification of predictive biomarkers and novel therapeutic targets, paving the way toward improving patient outcomes. Experimental Design: Parental breast cancer cells and their endocrine-resistant derivatives (EndoR) were used. Derivatives with acquired resistance to palbocidib (PalboR) were generated from parental and estrogen deprivation-resistant MCF7 and T47D cells. Transcriptomic and proteomic analyses were performed in palbociclib-sensitive and PalboR lines. Gene expression data from CDK4/6i neoadjuvant trials and publicly available datasets were interrogated for correlations of gene signatures and patient outcomes. Results: Parental and EndoR breast cancer lines showed varying degrees of sensitivity to palbociclib. Transcriptomic analysis of these cell lines identified an association between high IFN signaling and reduced CDK4/6i sensitivity; thus an "117 Nrelated palbociclib-resistance Signature" (IRPS) was derived. In two neoadjuvant trials of CDK4/6i plus endocrine therapy, IRPS and other IFN-related signatures were highly enriched in patients with tumors exhibiting intrinsic resistance to CDK4/6i. PalboR derivatives displayed dramatic activation of IFN/STATI signaling compared with their short-term treated or untreated counterparts. In primary ER+/HER2(-) tumors, the IRPS score was significantly higher in lumB than lumA subtype and correlated with increased gene expression of immune checkpoints, endocrine resistance, and poor prognosis. Conclusions: Aberrant IFN signaling is associated with intrinsic resistance to CDK4/6i. Experimentally, acquired resistance to palbociclib is associated with activation of the IFN pathway, warranting additional studies to clarify its involvement in resistance to CDK4/6i.
Keywords:	chemotherapy; radiation; endocrine therapy; expression; overexpression; mechanisms; pd-l1; signature; tool; palbociclib
Journal Title:	Clinical Cancer Research
Volume:	27
Issue:	17
ISSN:	1078-0432
Publisher:	American Association for Cancer Research
Date Published:	2021-09-01
Start Page:	4870
End Page:	4882
Language:	English
ACCESSION:	WOS:000692914500023
DOI:	10.1158/1078-0432.Ccr-19-4191
PROVIDER:	wos
PUBMED:	33536276
PMCID:	PMC8628647
Notes:	Erratum Issued, see DOI: 10.1158/1078-0432.CCR-21-2431 -- Article -- Source: Wos

https://synapse.mskcc.org/synapse/works/has_related_data_chk/187319