Resistance to HER2-Targeted Therapy

Theile, Dirk; Lenz, Gal; Momand, Jamil; Kane, Susan E.

doi:10.1007/978-3-319-70142-4_2

Cited by 2 publications

(2 citation statements)

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“…Because tDp/Dp32 leads to sustained phosphorylation of AKT in the presence of the Her2 inhibitor trastuzumab [34], it is thought that breast cancer cells are able to survive in the presence of trastuzumab. It bears mentioning that PI3K (upstream of AKT) frequently sustains activating mutations in cancers [38,40] that lead to phosphorylation of AKT in trastuzumab-resistant cancers; thus it is consistent that tDpmediated activation of AKT would also lead to resistance. There are other reported tDpmediated signaling pathways that may or may not be connected to AKT phosphorylation or trastuzumab resistance which we summarize below (see Table I).…”

Section: The Akt Pathwaymentioning

confidence: 83%

“…Due to AKT's central importance in tDp activity and cancer cell survival we will review the AKT signaling pathway from the perspective of its activation by Her2 (Figure 3). Her2 (ErbB2, neu) forms a dimer with either Her1 (EGFR, ErbB1), Her3 (ErbB3), or Her4 (ErbB4), with Her3 being its common partner [38]. Two signaling pathways emanate from the trans-phosphorylated cytoplasmic domains of Her2 and its receptor binding partner [39].…”

Section: The Akt Pathwaymentioning

confidence: 99%

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Darpp-32 and t-Darpp protein products of PPP1R1B: Old dogs with new tricks

Avanes

Lenz

Momand

2019

Biochemical Pharmacology

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The PPP1R1B gene is located on chromosome 17q12 (39,626,636,626[GRCh38/hg38]), which codes for multiple transcripts and two experimentally-documented proteins Darpp-32 and t-Darpp. Darpp-32 (Dopamine and cAMP Regulated Phosphoprotein), discovered in the early 1980s, is a protein whose phosphorylation is upregulated in response to cAMP in dopamineresponsive tissues in the brain. It's phosphorylation profile modulates its ability to bind and inhibit Protein Phosphatase 1 activity, which, in turn, controls the activity of hundreds of phosphorylated proteins. PPP1R1B knockout mice exhibit subtle learning defects. In 2002, the second protein product of PPP1R1B was discovered in gastric cancers: t-Darpp (truncated Darpp-32). The start codon of t-Darpp is amino acid residue 37 of Darpp-32 and it lacks the domain responsible for modulating Protein Phosphatase 1. Aside from gastric cancers, t-Darpp and/or Darpp-32 is overexpressed in tumor cells from breast, colon, esophagus, lung and prostate tissues. More than one research team has demonstrated that these proteins, through mechanisms that to date remain cloudy, activate AKT, a protein whose phosphorylation leads to cell survival and blocks apoptosis. Furthermore, in Her2 positive breast cancers (an aggressive form of breast cancer), t-Darpp/ Darpp-32 overexpression causes resistance to the frequently-administered anti-Her2 drug, trastuzumab (Herceptin), likely through AKT activation. Here we briefly describe how Darpp-32 and t-Darpp were discovered and report on the current state of knowledge of their involvement in cancers. We present a case for the development of an anti-t-Darpp therapeutic agent and outline the unique challenges this endeavor will likely encounter.

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Section: The Akt Pathwaymentioning

confidence: 83%

Section: The Akt Pathwaymentioning

confidence: 99%