HER family kinase domain mutations promote tumor progression and can predict response to treatment in human breast cancer

Abstract

Resistance to HER2-targeted therapies remains a major obstacle in the treatment of HER2-overexpressing breast cancer. Understanding the molecular pathways that contribute to the development of drug resistance is needed to improve the clinical utility of novel agents, and to predict the success of targeted personalized therapy based on tumor-specific mutations. Little is known about the clinical significance of HER family mutations in breast cancer. Because mutations within HER1/EGFR are predictive of response to tyrosine kinase inhibitors (TKI) in lung cancer, we investigated whether mutations in HER family kinase domains are predictive of response to targeted therapy in HER2-overexpressing breast cancer. We sequenced the HER family kinase domains from 76 HER2-overexpressing invasive carcinomas and identified 12 missense variants. Patients whose tumors carried any of these mutations did not respond to HER2 directed therapy in the metastatic setting. We developed mutant cell lines and used structural analyses to determine whether changes in protein conformation could explain the lack of response to therapy. We also functionally studied all HER2 mutants and showed that they conferred an aggressive phenotype and altered effects of the TKI lapatinib. Our data demonstrate that mutations in the finely tuned HER kinase domains play a critical function in breast cancer progression and may serve as prognostic and predictive markers.

Analysis of different HER‐2 mutations in breast cancer progression and drug resistance

“…However, HER‐2 activating mutations, another novel modus to activate HER‐2, have been reported 41, 42. Bose and his colleagues identified 16 HER‐2 somatic mutations though cancer genome sequencing in HER‐2 gene amplification‐negative breast cancer patients.…”

Recent Progress in HER2 Associated Breast Cancer

“…Finally, in the larger scale, Centrosome amplification (CA) amongst particular breast cancer subtypes (Her2+ subtype) is associated with genomic instability and aggressive tumor phenotypes., and Lee et al (2014) concluded CA, the precursor of chromosome instability and polyploidy correlates with amplification of the Her2 receptor, which affects over 20% breast cancer patients (Lee et al, 2014), In the study, they also clarified SGOL1 (Shugoshin proteins) is an attractive target for blocking the progression., when referred to the instability, we found another interesting outcome-HER family mutations in breast cancer may matter much, but until now, Little is known about the clinical significance, In the newest study of Delphine R et al HER2 mutants conferred an aggressive phenotype and altered effects of the TKI lapatinib (Boulbes et al, 2014), these coincided with JULIANN CHMIELECKI's declare that mutations can also activate the ERBB2/HER2 gene in breast, while at the same time be similarly sensitive to ERBB2/ HER2 inhibitors (Chmielecki et al, 2014). Joyfully, about the mutant mechanism, researchers newly reported a case that a breast cancer patient harboring an activating EGFR mutation clinically benefiting from EGFR-targeted treatment (Ali et al, 2014).…”

“…And the HER2 gene has been established as a valid biological marker for the treatment of breast cancer So far, Small Molecule Tyrosine Kinase Inhibitors of HER2 such as Trastuzumab, Pertuzumab, Lapatinib, Afatinib, AZD8931, AST-1306, AEE-788, CI-1033 (Canertinib), CP-724714, CUDC-101, TAK-285, AC-480 (BMS-599626), PF299804, PF299 (Dacomitinib), EKB-569 (Perlitinib) are on their way to clinical use or undergoing phase trials in aggressive breast cancer (Kumler et al, 2014;Schroeder et al, 2014), being explored for their potential to inhibit EGFR and HER2 tyrosine kinases. But we can't delay the fact that HER2 mediated resistance via multiple mechanisms is a common clinical problem (Boulbes et al, 2014;Leivonen et al, 2014). And treatment-induced toxicity, which can impair quality of life can't be ignored (Barroso-Sousa et al, 2013).…”

“…while novel Hsp90 (a bis-oxazolyl macrolide compound, which is known to stabilize and potentiate HER2 activity) inhibitor FW-04-806 alone or with laptinib inhibits cell proliferation, induces cell apoptosis and reduces the total and activated HER3 levels in these cells (Huang et al, 2014;, in the research of Huang et al (2014;, treatment with FW-04-806 showed a more favorable safety profile than the traditional Hsp90 inhibitors, since it didn't affect the ATPase, Now, the new HSP90 inhibitor 17-demethoxygeldanamycin (17AAG) is undergoing clinical testing in combination with trastuzumab, too (Boulbes et al, 2014). For all these mechanism, possible methods may have something to do with PI3K/Akt and Ras/MEK/ERK pathways (Huang et al, 2015), simultaneous treatment targeting at MAPKs and BIM with gefitinib and calcitriol or EB1089 in EGFR and HER2 positive-breast cancer cells proved to be significantly better to inhibit proliferation and induce apoptosis.…”

Non-HER2 signaling pathways activated in resistance to anti-HER2 therapy in breast cancer

“…Among the EGFR alterations, mutations in the kinase domain have been found in 7, 89 % of HER2-positive BC patients [21]. EGFR overexpression by IHC was positive in approximately 22.2 % (86/388) of BC patients [22].…”