Dataset Information

In vivo phosphoproteomics reveals kinase activity profiles that predict treatment outcome in triple-negative breast cancer

ABSTRACT: Triple-negative breast cancer (TNBC) lacks prognostic and predictive markers. We used high-throughput phosphoproteomics to build a functional TNBC taxonomy. A cluster of 159 phosphosites was upregulated in relapsed cases of a training set (n=34 patients). Eleven hyperactive kinases accounted for this phosphoprofile. A massspectrometry-to-immunohistochemistry translation step that assessed 113 TNBC validation specimens revealed that 6/12 kinases (PRKCE, KIT, PNKP, ERK, CDK6, and P70S6K) preserved independent prognostic value. The kinases split the validation set into two patterns: one (0/6 hyperactive kinases; 29% of the patients) associated with a 93.5% cure rate. The other (≥1 hyperactive kinase; 37 subpatterns) was associated with a 9.5-fold higher relapse risk. Each kinase pattern agglutinated different mutational patterns. Drug regimens designed based on these six kinases showed synergistic activity in vitro and in vivo. Our results elucidated novel phosphosites/kinases that are implicated in TNBC and provide a ready-to-use, actionable target-based clinical classification system for TNBC

INSTRUMENT(S): LTQ Orbitrap Elite

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Breast, Cell Culture

DISEASE(S): Breast Cancer

SUBMITTER: Javier Munoz

LAB HEAD: Miguel Quintela-Fandino

PROVIDER: PXD008012 | Pride | 2018-07-23

REPOSITORIES: Pride

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Source:

			Action	DRS
	20131217_OR8_RP_HP_C1.raw	Raw
	20131217_OR8_RP_HP_C10.raw	Raw
	20131217_OR8_RP_HP_C10_rr.raw	Raw
	20131217_OR8_RP_HP_C10b.raw	Raw
	20131217_OR8_RP_HP_C10b_rr.raw	Raw

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In vivo phosphoproteomics reveals kinase activity profiles that predict treatment outcome in triple-negative breast cancer.

Zagorac Ivana I Fernandez-Gaitero Sara S Penning Renske R Post Harm H Bueno Maria J MJ Mouron Silvana S Manso Luis L Morente Manuel M MM Alonso Soledad S Serra Violeta V Muñoz Javier J Gómez-López Gonzalo G Lopez-Acosta Jose Francisco JF Jimenez-Renard Veronica V Gris-Oliver Albert A Al-Shahrour Fatima F Piñeiro-Yañez Elena E Montoya-Suarez Jose Luis JL Apala Juan V JV Moreno-Torres Amalia A Colomer Ramon R Dopazo Ana A Heck Albert J R AJR Altelaar Maarten M Quintela-Fandino Miguel M

Nature communications 20180829 1

Triple-negative breast cancer (TNBC) lacks prognostic and predictive markers. Here, we use high-throughput phosphoproteomics to build a functional TNBC taxonomy. A cluster of 159 phosphosites is upregulated in relapsed cases of a training set (n = 34 patients), with 11 hyperactive kinases accounting for this phosphoprofile. A mass-spectrometry-to-immunohistochemistry translation step, assessing 2 independent validation sets, reveals 6 kinases with preserved independent prognostic value. The kina ...[more]

PMID: 30158526

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Project description:In this study the investigators looked at adaptive reprogramming impact on the kinome when a MEK inhibitor called GSK1120212 (trametinib) was administered in a "window of opportunity" trial. GSK1120212 is not yet approved by the FDA for use in breast cancer patients. The investigators gave GSK1120212 for a short period of time (one week) to examine MEK and the other kinase expression in cancer cells both before and after the study drug is given. The investigators gave this drug for research purposes only. The length of time it was given is not intended to treat cancer. Recently researchers at UNC developed a process that can comprehensively profile the majority of the individual kinases in the kinome and examine the impact on kinase expression of kinase inhibitors (Duncan et al, Cell 2012, PMID: 22500798). This can tell us which kinases need to be concurrently blocked to augment responsiveness and prevent acquired resistance so that the investigators can design the best combinations of kinase blocking drugs for triple negative breast cancer. This is especially important for individuals with triple negative breast cancer (TNBC) because there are no targeted drugs available that can block molecules that affect tumor growth. The investigators believe that kinase-blocking drugs have the potential to be a more effective treatment for people with TNBC. In this recently published study (Zawistowski et al, Cancer Discovery 2017, PMID: 28108460), TNBC patients treated with trametinib for 7 days resulted in a transcriptional response characterized by significant reprogramming of the tyrosine kinome, and this adaptive bypass response in human tumors was found to be similar to that seen in preclinical models including TNBC cell lines and mouse xenografts. In this study we also examined whether reprogramming differed between TNBC molecular subtypes, finding that basal-like and claudin-low human TNBC cells and mouse tumor subtypes had different adaptive transcriptional responses to MEK-ERK inhibition. Mechanistically we found that genome-wide enhancer remodeling drove the adaptive transcriptional response, suggesting that epigenetic approaches to reprogramming may be more durable than kinase inhibitor polypharmacology.