Inhibitor-induced HER2-HER3 heterodimerisation promotes proliferation through a novel dimer interface

Jeroen Claus, Gargi Patel, Flavia Autore, Audrey Colomba, Gregory Weitsman, Tanya N. Soliman, Selene Roberts, Laura C. Zanetti-Domingues, Michael Hirsch, Francesca Collu, Roger George, Elena Ortiz-Zapater, Paul R. Barber, Boris Vojnovic, Yosef Yarden, Marisa L. Martin-Fernandez, Angus Cameron, Franca Fraternali, Tony Ng, Peter J. Parker

نتاج البحث: نشر في مجلةمقالةمراجعة النظراء

ملخص

While targeted therapy against HER2 is an effective first-line treatment in HER2+ breast cancer, acquired resistance remains a clinical challenge. The pseudokinase HER3, heterodimerisation partner of HER2, is widely implicated in the resistance to HER2-mediated therapy. Here, we show that lapatinib, an ATP-competitive inhibitor of HER2, is able to induce proliferation cooperatively with the HER3 ligand neuregulin. This counterintuitive synergy between inhibitor and growth factor depends on their ability to promote atypical HER2-HER3 heterodimerisation. By stabilising a particular HER2 conformer, lapatinib drives HER2-HER3 kinase domain heterocomplex formation. This dimer exists in a head-to-head orientation distinct from the canonical asymmetric active dimer. The associated clustering observed for these dimers predisposes to neuregulin responses, affording a proliferative outcome. Our findings provide mechanistic insights into the liabilities involved in targeting kinases with ATP-competitive inhibitors and highlight the complex role of protein conformation in acquired resistance.

اللغة الأصليةالإنجليزيّة
رقم المقال32271
عدد الصفحات23
دوريةeLife
مستوى الصوت7
المعرِّفات الرقمية للأشياء
حالة النشرنُشِر - 1 مايو 2018

All Science Journal Classification (ASJC) codes

  • !!General Immunology and Microbiology
  • !!General Biochemistry, Genetics and Molecular Biology
  • !!General Neuroscience

بصمة

أدرس بدقة موضوعات البحث “Inhibitor-induced HER2-HER3 heterodimerisation promotes proliferation through a novel dimer interface'. فهما يشكلان معًا بصمة فريدة.

قم بذكر هذا