Hyperactivation of TORC1 drives resistance to the pan-HER tyrosine kinase inhibitor neratinib in HER2-mutant cancers

Sudhan, Dhivya R.; Guerrero-Zotano, Angel; Won, Helen; González Ericsson, Paula; Servetto, Alberto; Huerta-Rosario, Mariela; Ye, Dan; Lee, Kyung-min; Formisano, Luigi; Guo, Yan; Liu, Qi; Kinch, Lisa N.; Red Brewer, Monica; Dugger, Teresa; Koch, James; Wick, Michael J.; Cutler, Richard E.; Lalani, Alshad S.; Bryce, Richard; Auerbach, Alan; Hanker, Ariella B.; Arteaga, Carlos L.

doi:10.1016/j.ccell.2019.12.013

Cited by 49PI3K/AKT/mTOR signaling in cancerHER2/EGFR in Cancer ResearchLung Cancer Treatments and Mutations

Hyperactivation of TORC1 drives resistance to the pan-HER tyrosine kinase inhibitor neratinib in HER2-mutant cancers

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Sudhan, Dhivya R., Guerrero-Zotano, Angel, Won, Helen, González Ericsson, Paula, Servetto, Alberto, Huerta-Rosario, Mariela, Ye, Dan, Lee, Kyung-min +14 more·2020·Cancer Cell

DOI 10.1016/j.ccell.2019.12.013PMC PMC7301608

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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.

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Activation of the mTOR pathway plays a pivotal role in RTKi resistance.
“activation of the mTOR pathway plays a pivotal role in RTKi resistance [43]”
From Genome-wide CRISPR-cas9 knockout screening identifies GRB7 as a driver for MEK inhibitor resistance in KRAS mutant colon cancer (2022) · cites this paper as [43]

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Abstract 329: Hyperactivation of mTORC1 drives acquired resistance to the pan-HER tyrosine kinase inhibitor neratinib in HER2-mutant cancers
Sudhan, D. R., Zotano, Á. G., Won, H. H., Ericsson, P. G., Liu, Q., Dugger, T. C., Koch, J., Schram, A. M., Servetto, A., Cutler, R., et al. (2019) · Cancer Research · doi:10.1158/1538-7445.am2019-329
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Abstract 1828: Hyperactivation of mTORC1 drives acquired resistance to the pan HER tyrosine kinase inhibitor neratinib in HER2 mutant cancers
Sudhan, D. R., Hanker, A. B., Zotano, Á. G., Formisano, L., Guo, Y. P., Liu, Q., Avogadri-Connors, F., Cutler, R. E., Lalani, A. S., Bryce, R. P., et al. (2018) · Cancer Research · doi:10.1158/1538-7445.am2018-1828 · Cited by 1 · see citing works
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Abstract 1884: The activation of YES1 leads to the acquired resistance to neratinib in HER2-amplified breast and lung cancers
Yamamoto, H., Takeda, T., Suzawa, K., Tomida, S., Miyauchi, S., Araki, K., Nakata, K., Miura, A., Shien, T., Kitamura, Y., et al. (2020) · Cancer Research · doi:10.1158/1538-7445.am2020-1884
YES1 activation induces acquired resistance to neratinib in HER2‐amplified breast and lung cancers
Takeda, T., Yamamoto, H., Suzawa, K., Tomida, S., Miyauchi, S., Araki, K., Nakata, K., Miura, A., Namba, K., Shien, K., et al. (2019) · Cancer Science · doi:10.1111/cas.14289 · Cited by 23 · see citing works
Abstract P6-03-20: The development and characterization of novel HER2-positive breast cancer models of acquired neratinib resistance
Conlon, N. T., Browne, A. L., Breen, L., Eustace, A. J., Crown, J. P., & Collins, D. M. (2020) · Cancer Research · doi:10.1158/1538-7445.sabcs19-p6-03-20

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., Lalani, A. S., Bryce, R., Auerbach, A., Hanker, A. B., & Arteaga, C. L.
Affiliations: Harold C. Simmons Comprehensive Cancer Center (US)
Memorial Sloan Kettering Cancer Center (US)
Vanderbilt University Medical Center (US)
University of New Mexico (US)
Howard Hughes Medical Institute (US)
South Texas Accelerated Research Therapeutics (US)
Puma Biotechnology (United States) (US)
Corresponding author: Hanker, Ariella B.
Arteaga, Carlos L.
ORCID: Sudhan, Dhivya R.
Won, Helen
Servetto, Alberto
Huerta-Rosario, Mariela
Ye, Dan
Lee, Kyung-min
Formisano, Luigi
Guo, Yan
Liu, Qi
Kinch, Lisa N.
Wick, Michael J.
Cutler, Richard E.
Lalani, Alshad S.
Bryce, Richard
Hanker, Ariella B.
Arteaga, Carlos L.
Venue: Cancer Cell
Publisher: Elsevier BV
Published: 2020-02
Volume: 37
Issue: 2
Pages: 183-199.e5
ISSN: 1535-6108 (ISSN-L)
DOI: 10.1016/j.ccell.2019.12.013
PMC: PMC7301608
OpenAlex: W3002857006
Cited by: 49
References: 67
Citations by year: 2025: 2 · 2024: 10 · 2023: 9 · 2022: 11 · 2021: 10 · 2020: 6 · 2019: 1
FWCI: 2.92
Type: journal article
Language: en
Update notices: erratum (2020-02-10)
Open access: bronze
doi.org
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/legal/tdmrep-license (tdm)
www.elsevier.com/open-access/userlicense/1.0/ (vor, 375 d)
doi.org/10.15223/policy-017 (stm-asf)
doi.org/10.15223/policy-037 (stm-asf)
doi.org/10.15223/policy-012 (stm-asf)
doi.org/10.15223/policy-029 (stm-asf)
doi.org/10.15223/policy-004 (stm-asf)
Locations: Cancer Cell (publishedVersion)
PubMed (publishedVersion)
Europe PMC (PubMed Central) (acceptedVersion)
PubMed Central (acceptedVersion)
Funders: Cancer Prevention and Research Institute of Texas
National Cancer Institute (P50 CA098131, 5P30CA142543)
Vanderbilt-Ingram Cancer Center (P30 CA68485)
Breast Cancer Research Foundation
Susan G. Komen (5P30CA142543, SAC100013)
University of Texas Southwestern Medical Center (P30 CA142543)
Takeda Pharmaceuticals U.S.A.
Pfizer
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
Health Sciences › Medicine › Oncology › HER2/EGFR in Cancer Research
Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
Keywords: neratinib, drug resistance, TORC1 signaling, mTOR signaling, Ras signaling, raptors, Rheb, S6 phosphorylation, patient-derived xenografts, organoids, circulating tumor DNA, HER2 tyrosine kinase inhibitor
MeSH terms: Mechanistic Target of Rapamycin Complex 1, Breast Neoplasms, Humans, Quinolines, Signal Transduction, Receptor, ErbB-2, Erb-b2 Receptor Tyrosine Kinases, Drug Resistance, Neoplasm, Cell Line, Tumor, Protein Kinase Inhibitors

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Hyperactivation of TORC1 drives resistance to the pan-HER tyrosine kinase inhibitor neratinib in HER2-mutant cancers

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