Clinical Implications of Sub-grouping HER2 Positive Tumors by Amplicon Structure and Co-amplified Genes

Abstract

ERBB2 amplification is a prognostic marker for aggressive tumors and a predictive marker for prolonged survival following treatment with HER2 inhibitors. We attempt to sub-group HER2+ tumors based on amplicon structures and co-amplified genes. We examined five HER2+ cell lines, three HER2+ xenographs and 57 HER2+ tumor tissues. ERBB2 amplification was analyzed using digital droplet PCR and low coverage whole genome sequencing. In some HER2+ tumors PPM1D, that encodes WIP1, is co-amplified. Cell lines were treated with HER2 and WIP1 inhibitors. We find that inverted duplication is the amplicon structure in the majority of HER2+ tumors. In patients suffering from an early stage disease the ERBB2 amplicon is composed of a single segment while in patients suffering from advanced cancer the amplicon is composed of several different segments. We find robust WIP1 inhibition in some HER2+ PPM1D amplified cell lines. Sub-grouping HER2+ tumors using low coverage whole genome sequencing identifies inverted duplications as the main amplicon structure and based on the number of segments, differentiates between local and advanced tumors. In addition, we found that we could determine if a tumor is a recurrent tumor or second primary tumor and identify co-amplified oncogenes that may serve as targets for therapy.

Epidermal stem cells participate in the repair of scalds via Nanog and Myc regulation

“…Myc is a transcription factor that regulates cell proliferation ( 33 ). Moreover, Myc is widely expressed during embryogenesis, but also in highly proliferative adult tissues, such as the epidermis and gut ( 34 ).…”

Novel Therapies and Strategies to Overcome Resistance to Anti-HER2-Targeted Drugs

“…Aside GSDMs, there are other frequently amplified genes near the HER2 amplicon that could affect HER2 BC clinical behavior, such as TOP2A (in 17q21.2 [ 192 ]) or genes within the 17q23 amplicon such as RPS6KB1 , PPM1D , or MIR21 [ 193 , 194 ]. PPM1D (located at the 17q23 region) encodes the wildtype p53-induced phosphatase1 (WIP1), a protein that negatively regulates p53 function, enhances cell cycle progression, and accelerates tumor incidence in HER2 BC mouse models [ 195 ].…”

“…PPM1D (located at the 17q23 region) encodes the wildtype p53-induced phosphatase1 (WIP1), a protein that negatively regulates p53 function, enhances cell cycle progression, and accelerates tumor incidence in HER2 BC mouse models [ 195 ]. In HER2/WIP1-amplified tumors, pharmacological WIP1 inhibition reduced cell proliferation and, importantly, also partially restored sensitivity to trastuzumab [ 193 , 194 ], thus suggesting that the WIP1 oncogene could be another potential therapeutic target to reverse anti-HER2 therapy resistance.…”

Renaissance of armored immune effector cells, CAR-NK cells, brings the higher hope for successful cancer therapy

“…ErbB2 has also been incorporated in CARengineered NK-92 cells to be evaluated in cancer experiments [153]. It was found that ErbB2 is overexpressed in some types of human tumors with an epithelial origin and it is thought that it has a role in cancer development and progression [4,154]. Several CAR-engineering approaches capable of targeting the ErbB2-positive cancers are now in development process.…”

“…Cancer immunotherapy exploits the body’s immune system to fight against cancer and is classified by three branches: immune checkpoint inhibitors (ICIs), adoptive cell therapies (ACTs), and tumor vaccines [ 2 , 3 ]. Cancer immunotherapy can help patients with advanced tumors or recurrent cancers [ 4 ].…”