why adding cdk4/6inhibitor palbociclib 2herceptin should minimize chances of develop-

[Lani]

ing resistance to herceptin
Cancer Res. 2016 Feb 1. pii: canres.2383.2015. [Epub ahead of print]
HER2 signaling drives DNA anabolism and proliferation through SRC-3 phosphorylation and E2F1-regulated gene expression programs.
Nikolai BC1, Lanz RB1, York B1, Dasgupta S1, Mitsiades N2, Creighton CJ3, Tsimelzon A4, Hilsenbeck SG4, Lonard DM1, Smith CL1, O'Malley BW5.
Author information
1Molecular and Cellular Biology, Baylor College of Medicine.
2Medicine and Molecular and Cellular Biology, Baylor College of Medicine.
3Department of Medicine and Dan L. Duncan Cancer Center, Baylor College of Medicine.
4Lester & Sue Smith Breast Center, Baylor College of Medicine.
5Molecular and Cellular Biology, Baylor College of Medicine berto@bcm.edu.
Abstract
Approximately 20% of early-stage breast cancers display amplification or overexpression of the ErbB2/HER2 oncogene, conferring poor prognosis and resistance to endocrine therapy. Targeting HER2+ tumors with trastuzumab or the receptor tyrosine kinase (RTK) inhibitor lapatinib significantly improves survival, yet tumor resistance and progression of metastatic disease still develop over time. While the mechanisms of cytosolic HER2 signaling are well studied, nuclear signaling components and gene regulatory networks that bestow therapeutic resistance and limitless proliferative potential are incompletely understood. Here, we use biochemical and bioinformatic approaches to identify effectors and targets of HER2 transcriptional signaling in human breast cancer. Phosphorylation and activity of the Steroid Receptor Coactivator-3 (SRC-3) is reduced upon HER2 inhibition, and recruitment of SRC-3 to regulatory elements of endogenous genes is impaired. Transcripts regulated by HER2 signaling are highly enriched with E2F1 binding sites and define a gene signature associated with proliferative breast tumor subtypes, cell cycle progression, and DNA replication. We show that HER2 signaling promotes breast cancer cell proliferation through regulation of E2F1-driven DNA metabolism and replication genes together with phosphorylation and activity of the transcriptional coactivator SRC-3. Furthermore, our analyses identified a cyclin dependent kinase (CDK) signaling node that, when targeted using the CDK4/6 inhibitor Palbociclib, defines overlap and divergence of adjuvant pharmacological targeting. Importantly, lapatinib and palbociclib strictly block de novo synthesis of DNA, mostly through disruption of E2F1 and its target genes. These results have implications for rational discovery of pharmacological combinations in pre-clinical models of adjuvant treatment and therapeutic resistance.
Copyright © 2016, American Association for Cancer Research.
PMID: 26833126 [PubMed - as supplied by publisher]

[agness]

Cool. Well, that's my impression. I'm glad they are learning new things.

A gal with brain mets on breastcancer.org tested positive for PI3KCA, something associated with a non-PCR and possible resistance in HER2+ patients.

There might be ways to overcome the resistance but it will take other drugs and also patient-driven alternative treatment additions to move the needle so to speak. Standard of care gets stuck but with hyperbaric oxygen, water-based fasting, IV curcumin, and other supplements that cancer metabolism might be altered.

Some links:

Network of PIK3CA mutations may affect response to HER-2–targeted therapies
http://www.healio.com/hematology-onc...eted-therapies

Cell Death and Disease - Clinical update on cancer: molecular oncology of head and neck cancer (Scroll halfway down for suggestions for ways to shift resistance)
http://www.nature.com/cddis/journal/...s2013548a.html