Archives

  • 2018-07
  • 2019-04
  • 2019-05
  • 2019-06
  • 2019-07
  • 2019-08
  • 2019-09
  • 2019-10
  • 2019-11
  • 2019-12
  • 2020-01
  • 2020-02
  • 2020-03
  • 2020-04
  • 2020-05
  • 2020-06
  • 2020-07
  • 2020-08
  • 2020-09
  • 2020-10
  • 2020-11
  • 2020-12
  • 2021-01
  • 2021-02
  • 2021-03
  • 2021-04
  • 2021-05
  • 2021-06
  • 2021-07
  • 2021-08
  • 2021-09
  • 2021-10
  • 2021-11
  • 2021-12
  • 2022-01
  • 2022-02
  • 2022-03
  • 2022-04
  • 2022-05
  • 2022-06
  • 2022-07
  • 2022-08
  • br Conclusion In conclusion HER CTCs can

    2022-08-05


    Conclusion In conclusion, HER2+ CTCs can be detected using the LiquidBiopsy system. Among the patients with histologically HER2+ breast cancer, 41.9% had ≥ 1 HER2+ CTC/4 mL of blood. The cell lines experiments showed high sensitivity (100%) and specificity (99.9%) using a HER2/CD45 fluorescence ratio of 3.5.
    Disclosure This study was funded by Zhuhai Livzon Cynvenio Diagnostics Ltd. The authors have stated that they have no conflicts of interest.
    Acknowledgments
    Significance We have identified several recurrent actionable activating HER2 TMD and JMD mutants in patient tumors from multiple cancers. Our data indicate that patients with HER2 TMD/JMD mutant are likely candidates for approved HER2-targeted therapies. Based on the mutation frequency, we estimate >6,000 TMD/JMD mutant cancer patients are likely to benefit annually from targeted HER2 therapy. Our findings will aid in the implementation of precision medicine in cancer by matching patient mutations with targeted therapy.
    Introduction The human epidermal growth factor receptor (HER) tyrosine kinase family consists of ERBB1/EGFR/HER1, ERBB2/HER2, ERBB3/HER3, and ERBB4/HER4. These receptors play an important role in cellular processes including growth, proliferation, differentiation, and survival (Baselga and Swain, 2009, Hynes and Lane, 2005). ERBB receptors contain an extracellular domain (ECD), a transmembrane domain (TMD), an intracellular region that consists of a juxtamembrane domain (JMD), a kinase domain (KD), and a C-terminal tail domain (CTD) (Kovacs et al., 2015). The ECD is comprised of four subdomains (I–IV). In the absence of ligand, the ECD adopts an auto-inhibited tethered (closed) conformation that involves domains II and IV. Upon ligand binding between domains I and III, the dimerization arm in domain II is untethered, leading to receptor homo or heterodimerization, allosteric kinase activation, CTD phosphorylation and downstream signaling (Kovacs et al., 2015). HER2 is an atypical member of the ERBB family, as its ECD adopts an untethered conformation constitutively (Roskoski, 2014). Unlike the other ERBB family members, HER2 does not have a ligand. HER2 preferentially heterodimerizes with ligand bound untethered (open) HER3 or EGFR to initiate cellular signaling, although HER2 homodimers capable of signaling have been reported in HER2 overexpressing ICI 118,551 hydrochloride (Brennan et al., 2000, Roskoski, 2014). The transforming ability of HER2 was originally discovered in a nitrosoethylurea (neu)-induced glioblastoma rat model (Schubert et al., 1974, Schechter et al., 1985). Cloning and analysis of the HER2 sequence in this model revealed a Val to Glu mutation at codon 664 (V664E; V659E in humans) in the TMD of HER2 (Bargmann et al., 1986). Subsequent studies showed amplification and overexpression of the HER2 gene (ERBB2) as the oncogenic driver in ∼20% of human breast and gastric cancers (Roskoski, 2014). Its established role as a potent oncogene has made HER2 a major target for therapy (Stern, 2012). Three HER2 antibody drugs trastuzumab, ado-trastuzumab emtansine (T-DM1), and pertuzumab, and two small-molecule HER2 kinase inhibitors lapatinib and neratinib, have been approved by the US Food and Drug Administration (FDA) for use in the clinic for treating HER2-driven tumors (Gianni, 2018). While overexpression remains a major mechanism of HER2-driven tumorigenesis, recent large-scale sequencing efforts have identified oncogenic mutations in the ECD and KD (Greulich et al., 2012, Zabransky et al., 2015, Ross et al., 2016). Mutations in the TMD and JMD have also been reported, albeit at a low frequency, and their relevance in oncogenesis is not fully understood (Bose et al., 2013, Yamamoto et al., 2014, Kavuri et al., 2015, Ou et al., 2017, Chang et al., 2018).
    Results
    Discussion Analysis of sequence data from ∼111,000 tumors representing ∼400 cancer types identified many recurrent somatic mutations in the TMD and JMD of HER2 that included G660D, V659E, R678Q, and Q709L. Functional analysis of the mutants observed in patients showed that a majority of the recurrent mutations were activating and are likely drivers. Both V659 and G660 are part of the N-terminal S656-xxx-G660 motif in the HER2 TMD important for receptor dimerization, kinase activation, and signaling (Arkhipov et al., 2013, Endres et al., 2013, Fleishman et al., 2002, Ou et al., 2017). We observed a striking relationship between the chemical nature of the TMD mutations and the potency with which they activate HER2. Substitutions to polar residues (S653C, V659E, G660D/R, and E693K) exert a much stronger activating effect on HER2 than apolar mutations (L651V, V659G, and L674V). These polar mutations cluster at the N terminus of the TMD, extending the existing stretch of polar residues on one face of the amphiphilic transmembrane helix. The significance of this pattern is unclear, but our MD data suggest that polar residues support rearrangements of the TMD helices and deviation from the N-terminally mediated dimer, a phenomenon that has previously been observed in other membrane proteins carrying polar TMD mutations (Brooks et al., 2014, Goldberg et al., 2010, Gordeliy et al., 2002).