These alterations included genetic loss of the RAS-GAP NF1 (8% of metastatic tumors) and activating mutations in ERBB2 (7% of metastatic tumors). 1a, S1b–d) in metastatic samples as compared to primary tumors ( p = 0.020) (Fig. We also found a significant enrichment of mutations known to activate RAS-MAPK signaling (Figs. As expected, we identified concurrent mutations in the PI3K/AKT pathway including in PIK3CA (30%), PTEN (2.6%), and AKT1 (0.3%) 18. To interrogate the signaling mechanisms underlying resistance to HER2-targeted therapies, we performed genomic sequencing analysis on a cohort of 733 ERBB2-amplified primary and metastatic breast tumors (Fig. MAPK pathway alterations in advanced, treatment refractory HER2 + breast cancer Intriguingly, we find an enrichment of MAPK pathway mutations in advanced cancers and demonstrate that these alterations can promote a switch in pathway dependence from PI3K/AKT to MEK/ERK, lead to resistance to anti-HER2 therapies, and sensitize these cancers to MEK/ERK inhibitors. Here, we define the genomic landscape of HER2 + breast cancer including both primary, treatment-naïve tumors as well as anti-HER2 treatment-refractory metastatic tumors. However, these alterations have proven neither binary markers of sensitivity nor sufficiently comprehensive to elucidate the basis for resistance in the majority of patients. Moreover, genomic alterations in the cell regulators p27 21, cyclin E 22, and cyclin D/CDK4 23 have also been implicated in resistance to HER2-targeted therapies. Both preclinical and early clinical data have suggested that activating mutations in the PI3K pathway ( PIK3CA mutation, PTEN loss, or ERBB3 mutation) reduce the efficacy of anti-HER2 treatments 15, 16, 17, 18, 19, 20. More recently, combinations of anti-HER2 therapies together with additional drugs to downregulate the PI3K/AKT pathway (pertuzumab, alpelisib, everolimus) have been advanced in the clinic on the basis of this work.ĭespite the clinical success of HER2/HER3/PI3K-targeted therapies in breast cancer treatment, de novo and acquired resistance nonetheless occurs, particularly in the metastatic setting 13, 14. This marked pathway dependence has been attributed to the entrainment of multiple cell cycle regulators including cyclin D1 and p27 by AKT in this context 6, 7, 8, 9, 10, 11, 12. Indeed, PI3K/AKT inhibitors, but not MEK/ERK inhibitors, have major antitumor effects in models of HER2-amplified breast cancer 2, 3, 4, 5.
![graphpad prism 6 key graphpad prism 6 key](https://img.informer.com/p6/graphpad-prism-v6-main-window-display.png)
The efficacy of HER2-targeted therapies specifically hinges upon their ability to inhibit PI3K signaling 1, despite activation of multiple other pathways by the receptor, including the ERK pathway. The discovery and pharmacologic inhibition of the HER2/neu oncogene in breast cancer represents a hallmark success in targeted therapy in oncology. These results establish genetic activation of MAPK as a recurrent mechanism of anti-HER2 therapy resistance that may be effectively combated with MEK/ERK inhibitors.
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#Graphpad prism 6 key driver
Mechanistically, this driver pathway switch is a result of MEK-dependent activation of CDK2 kinase. Moreover, resistant tumors lose AKT dependence while undergoing a dramatic sensitization to MEK/ERK inhibition. These mutations, including NF1 loss and ERBB2 activating mutations, are sufficient to mediate resistance to FDA-approved HER2 kinase inhibitors including tucatinib and neratinib. Through genomic profiling of 733 HER2-amplified breast cancers, we identify enrichment of somatic alterations that promote MEK/ERK signaling in metastatic tumors with shortened progression-free survival on anti-HER2 therapy.
![graphpad prism 6 key graphpad prism 6 key](https://www.researchgate.net/profile/Bui-Duy-2/post/How-to-input-data-to-determine-IC50-of-an-enzyme-inhibition-assay-from-absorbance-data-by-Graphpad-Prism/attachment/5ef19d195225fb0001217c37/AS%3A905469958828032%401592892269488/image/data.png)
![graphpad prism 6 key graphpad prism 6 key](http://softwaredownloadcracked.com/wp-content/uploads/2014/03/qq26.jpg)
Whilst resistance to HER2 inhibition is common in the metastatic setting, the specific programs downstream of HER2 driving resistance are not established. Inhibition of HER2 in HER2-amplified breast cancer has been remarkably successful clinically, as demonstrated by the efficacy of HER-kinase inhibitors and HER2-antibody treatments.