Hyperactivation of TORC1 drives resistance to the pan-HER tyrosine kinase inhibitor neratinib in HER2-mutant cancers Journal Article
| Authors: | Sudhan, D. R.; Guerrero-Zotano, A.; Won, H.; González Ericsson, P.; Servetto, A.; Huerta-Rosario, M.; Ye, D.; Lee, K. M.; Formisano, L.; Guo, Y.; Liu, Q.; Kinch, L. N.; Red Brewer, M.; Dugger, T.; Koch, J.; Wick, M. J.; Cutler, R. E. Jr; Lalani, A. S.; Bryce, R.; Auerbach, A.; Hanker, A. B.; Arteaga, C. L. |
| Article Title: | Hyperactivation of TORC1 drives resistance to the pan-HER tyrosine kinase inhibitor neratinib in HER2-mutant cancers |
| Abstract: | We developed neratinib-resistant HER2-mutant cancer cells by gradual dose escalation. RNA sequencing identified TORC1 signaling as an actionable mechanism of drug resistance. Primary and acquired neratinib resistance in HER2-mutant breast cancer patient-derived xenografts (PDXs) was also associated with TORC1 hyperactivity. Genetic suppression of RAPTOR or RHEB ablated P-S6 and restored sensitivity to the tyrosine kinase inhibitor. The combination of the TORC1 inhibitor everolimus and neratinib potently arrested the growth of neratinib-resistant xenografts and organoids established from neratinib-resistant PDXs. RNA and whole-exome sequencing revealed RAS-mediated TORC1 activation in a subset of neratinib-resistant models. DNA sequencing of HER2-mutant tumors clinically refractory to neratinib, as well as circulating tumor DNA profiling of patients who progressed on neratinib, showed enrichment of genomic alterations that converge to activate the mTOR pathway. © 2019 Elsevier Inc. In brief, Sudhan et al. identify that hyperactivation of TORC1 restores HER2 downstream signaling to drive neratinib resistance across histologically distinct HER2-mutant cancers. The combination of TORC1 inhibitor everolimus and neratinib arrests the growth of neratinib-resistant cells, organoids, and xenografts. © 2019 Elsevier Inc. |
| Keywords: | controlled study; nonhuman; mouse; animal tissue; breast cancer; epidermal growth factor receptor 2; animal experiment; animal model; tumor xenograft; drug resistance; cancer resistance; cancer inhibition; dna; gene repression; dna sequence; everolimus; neratinib; mammalian target of rapamycin complex 1; rheb protein; female; priority journal; article; torc1; whole exome sequencing; her2 mutations; organoid; precision oncology; regulatory associated protein of mtor |
| Journal Title: | Cancer Cell |
| Volume: | 37 |
| Issue: | 2 |
| ISSN: | 1535-6108 |
| Publisher: | Cell Press |
| Date Published: | 2020-02-10 |
| Start Page: | 183 |
| End Page: | 199.e5 |
| Language: | English |
| DOI: | 10.1016/j.ccell.2019.12.013 |
| PUBMED: | 31978326 |
| PROVIDER: | scopus |
| PMCID: | PMC7301608 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 2 March 2020 -- Source: Scopus |
