TY - JOUR
T1 - RET inhibition in novel patient-derived models of RET fusion-positive lung adenocarcinoma reveals a role for MYC upregulation
AU - Hayashi, Takuo
AU - Odintsov, Igor
AU - Smith, Roger S.
AU - Ishizawa, Kota
AU - Liu, Allan J.W.
AU - Delasos, Lukas
AU - Kurzatkowski, Christopher
AU - Tai, Huichun
AU - Gladstone, Eric
AU - Vojnic, Morana
AU - Kohsaka, Shinji
AU - Suzawa, Ken
AU - Liu, Zebing
AU - Kunte, Siddharth
AU - Mattar, Marissa S.
AU - Khodos, Inna
AU - Davare, Monika A.
AU - Drilon, Alexander
AU - Cheng, Emily
AU - de Stanchina, Elisa
AU - Ladanyi, Marc
AU - Somwar, Romel
N1 - Funding Information:
T.H., I.O., R.S.S., K.I., Z.L., A.J.W.L., C.K., H.T., S. Kohsaka, K.S., M.V., L.D., M.S., E.G., S. Kunte, I.K., M.A.D., E.d.S. and E.C. report no potential conflict of interest. A.D. reports consulting/advisory roles for Ignyta, Loxo Oncology, TP Therapeutics, AstraZeneca, Pfizer, Blueprint Medicines, Genentech/Roche, Helsinn Therapeutics, BeiGene, Hengrui Therapeutics, Exelixis, Bayer, Tyra Biosciences, Verastem, Takeda/Millennium, BerGenBio, MORE Health, Eli Lilly and Company, and Verastem; royalties for Pocket Oncology; honoraria from Medscape, OncLive, PeerVoice, Physician’s Education Resource, Targeted Oncology, MORE Health, Research to Practice, Foundation Medicine, and Peerview; and research funding from Foundation Medicine. M.L. has received advisory board compensation from Boehringer Ingelheim, AstraZeneca, Bristol-Myers Squibb, Takeda, Bayer, and Paige.AI, and research support from LOXO Oncology, Helsinn Healthcare, Elevation Oncology and Merus. R.S. has received research funding from Merus, Helsinn Healthcare, LOXO Oncology and Elevation Oncology for studies unrelated to this paper.
Funding Information:
This work was supported by a grant from the Stanley and Fiona Druckenmiller Center for Lung Cancer Research at Memorial Sloan Kettering Cancer Center, (to R.S., A.D., M.L.), P01 CA129243 from the National Institutes of Health (to M.L.), a U54 OD020355 grant from the National Institutes of Health to E.d.S. and a Memorial Sloan Kettering Cancer Center Support Grant (P30 CA008748).
Publisher Copyright:
© 2021. Published by The Company of Biologists Ltd
PY - 2021/2
Y1 - 2021/2
N2 - Multi-kinase RET inhibitors, such as cabozantinib and RXDX-105, are active in lung cancer patients with RET fusions; however, the overall response rates to these two drugs are unsatisfactory compared to other targeted therapy paradigms. Moreover, these inhibitors may have different efficacies against RET rearrangements depending on the upstream fusion partner. A comprehensive preclinical analysis of the efficacy of RET inhibitors is lacking due to a paucity of disease models harboring RET rearrangements. Here, we generated two new patient-derived xenograft (PDX) models, one new patient-derived cell line, one PDX-derived cell line, and several isogenic cell lines with RET fusions. Using these models, we re-examined the efficacy and mechanism of action of cabozantinib and found that this RET inhibitor was effective at blocking growth of cell lines, activating caspase 3/7 and inhibiting activation of ERK and AKT. Cabozantinib treatment of mice bearing RET fusion-positive cell line xenografts and two PDXs significantly reduced tumor proliferation without adverse toxicity. Moreover, cabozantinib was effective at reducing growth of a lung cancer PDX that was not responsive to RXDX-105. Transcriptomic analysis of lung tumors and cell lines with RET alterations showed activation of a MYC signature and this was suppressed by treatment of cell lines with cabozantinib. MYC protein levels were rapidly depleted following cabozantinib treatment. Taken together, our results demonstrate that cabozantinib is an effective agent in preclinical models harboring RET rearrangements with three different 5′ fusion partners (CCDC6, KIF5B and TRIM33). Notably, we identify MYC as a protein that is upregulated by RET expression and downregulated by treatment with cabozantinib, opening up potentially new therapeutic avenues for the combinatorial targetin of RET fusion-driven lung cancers. The novel RET fusion-dependent preclinical models described here represent valuable tools for further refinement of current therapies and the evaluation of novel therapeutic strategies.
AB - Multi-kinase RET inhibitors, such as cabozantinib and RXDX-105, are active in lung cancer patients with RET fusions; however, the overall response rates to these two drugs are unsatisfactory compared to other targeted therapy paradigms. Moreover, these inhibitors may have different efficacies against RET rearrangements depending on the upstream fusion partner. A comprehensive preclinical analysis of the efficacy of RET inhibitors is lacking due to a paucity of disease models harboring RET rearrangements. Here, we generated two new patient-derived xenograft (PDX) models, one new patient-derived cell line, one PDX-derived cell line, and several isogenic cell lines with RET fusions. Using these models, we re-examined the efficacy and mechanism of action of cabozantinib and found that this RET inhibitor was effective at blocking growth of cell lines, activating caspase 3/7 and inhibiting activation of ERK and AKT. Cabozantinib treatment of mice bearing RET fusion-positive cell line xenografts and two PDXs significantly reduced tumor proliferation without adverse toxicity. Moreover, cabozantinib was effective at reducing growth of a lung cancer PDX that was not responsive to RXDX-105. Transcriptomic analysis of lung tumors and cell lines with RET alterations showed activation of a MYC signature and this was suppressed by treatment of cell lines with cabozantinib. MYC protein levels were rapidly depleted following cabozantinib treatment. Taken together, our results demonstrate that cabozantinib is an effective agent in preclinical models harboring RET rearrangements with three different 5′ fusion partners (CCDC6, KIF5B and TRIM33). Notably, we identify MYC as a protein that is upregulated by RET expression and downregulated by treatment with cabozantinib, opening up potentially new therapeutic avenues for the combinatorial targetin of RET fusion-driven lung cancers. The novel RET fusion-dependent preclinical models described here represent valuable tools for further refinement of current therapies and the evaluation of novel therapeutic strategies.
KW - MYC
KW - NSCLC
KW - RET fusion PDX
KW - RET inhibitor
KW - Transcriptome profiling
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U2 - 10.1242/dmm.047779
DO - 10.1242/dmm.047779
M3 - Article
C2 - 33318047
AN - SCOPUS:85101154278
VL - 14
JO - DMM Disease Models and Mechanisms
JF - DMM Disease Models and Mechanisms
SN - 1754-8403
IS - 2
M1 - dmm047779
ER -