Ligand-independent HER2/HER3/PI3K Complex is Disrupted by Trastuzumab and is Effectively Inhibited by the PI3K Inhibitor GDC-0941

Overview

Journal Cancer Cell

Publisher Cell Press

Specialty Oncology

Date 2009 May 5

PMID 19411071

Citations 394

Authors

Teemu T Junttila

Robert W Akita

Kathryn Parsons

Carter Fields

Gail D Lewis Phillips

Lori S Friedman

Deepak Sampath

Mark X Sliwkowski

Affiliations

Soon will be listed here.

Abstract

Herceptin (trastuzumab) is the backbone of HER2-directed breast cancer therapy and benefits patients in both the adjuvant and metastatic settings. Here, we describe a mechanism of action for trastuzumab whereby antibody treatment disrupts ligand-independent HER2/HER3 interactions in HER2-amplified cells. The kinetics of dissociation parallels HER3 dephosphorylation and uncoupling from PI3K activity, leading to downregulation of proximal and distal AKT signaling, and correlates with the antiproliferative effects of trastuzumab. A selective and potent PI3K inhibitor, GDC-0941, is highly efficacious both in combination with trastuzumab and in the treatment of trastuzumab-resistant cells and tumors.

Citing Articles

Emerging importance of HER3 in tumorigenesis and cancer therapy.

Garrett J, Tendler S, Feroz W, Kilroy M, Yu H Nat Rev Clin Oncol. 2025; .

PMID: 40087402 DOI: 10.1038/s41571-025-01008-y.

Targeting the PI3K/AKT/mTOR pathway in lung cancer: mechanisms and therapeutic targeting.

Qiang M, Chen Z, Liu H, Dong J, Gong K, Zhang X Front Pharmacol. 2025; 16:1516583.

PMID: 40041495 PMC: 11877449. DOI: 10.3389/fphar.2025.1516583.

Semaphorin 3F inhibits breast cancer metastasis by regulating the Akt-mTOR and TGFβ signaling pathways via neuropilin-2.

Nakayama H, Murakami A, Nishida-Fukuda H, Fukuda S, Matsugi E, Nakahara M Sci Rep. 2025; 15(1):7394.

PMID: 40033046 PMC: 11876635. DOI: 10.1038/s41598-025-91559-y.

PIK3CA gene mutation status associated with poor prognosis of breast cancer: a retrospective cohort study.

Yan M, Zong Z, Guo W, Li X, Li J, Xia X BMC Cancer. 2025; 25(1):365.

PMID: 40016671 PMC: 11869396. DOI: 10.1186/s12885-025-13486-5.

Intratumour oxidative hotspots provide a niche for cancer cell dissemination.

Ueda Y, Kiyonaka S, Selfors L, Inoue K, Harada H, Doura T Nat Cell Biol. 2025; 27(3):530-543.

PMID: 39984655 DOI: 10.1038/s41556-025-01617-w.