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Therapeutic targeting of the mevalonate-geranylgeranyl diphosphate pathway with statins overcomes chemotherapy resistance in small cell lung cancer

Guo, Chenchen; Wan, Ruijie; He, Yayi; Lin, Shu-Hai; Cao, Jiayu; Qiu, Ying; Zhang, Tengfei; Zhao, Qiqi; Niu, Yujia; Jin, Yujuan; Huang, Hsin-Yi; Wang, Xue; Tan, Li; Thomas, Roman K; Zhang, Hua; Chen, Luonan; Wong, Kwok-Kin; Hu, Liang; Ji, Hongbin
Small cell lung cancer (SCLC) lacks effective treatments to overcome chemoresistance. Here we established multiple human chemoresistant xenograft models through long-term intermittent chemotherapy, mimicking clinically relevant therapeutic settings. We show that chemoresistant SCLC undergoes metabolic reprogramming relying on the mevalonate (MVA)-geranylgeranyl diphosphate (GGPP) pathway, which can be targeted using clinically approved statins. Mechanistically, statins induce oxidative stress accumulation and apoptosis through the GGPP synthase 1 (GGPS1)-RAB7A-autophagy axis. Statin treatment overcomes both intrinsic and acquired SCLC chemoresistance in vivo across different SCLC PDX models bearing high GGPS1 levels. Moreover, we show that GGPS1 expression is negatively associated with survival in patients with SCLC. Finally, we demonstrate that combined statin and chemotherapy treatment resulted in durable responses in three patients with SCLC who relapsed from first-line chemotherapy. Collectively, these data uncover the MVA-GGPP pathway as a metabolic vulnerability in SCLC and identify statins as a potentially effective treatment to overcome chemoresistance.
PMID: 35449308
ISSN: 2662-1347
CID: 5218552

Ontogeny and Vulnerabilities of Drug-Tolerant Persisters in HER2+ Breast Cancer

Chang, Chewei Anderson; Jen, Jayu; Jiang, Shaowen; Sayad, Azin; Mer, Arvind Singh; Brown, Kevin R; Nixon, Allison M L; Dhabaria, Avantika; Tang, Kwan Ho; Venet, David; Sotiriou, Christos; Deng, Jiehui; Wong, Kwok-Kin; Adams, Sylvia; Meyn, Peter; Heguy, Adriana; Skok, Jane A; Tsirigos, Aristotelis; Ueberheide, Beatrix; Moffat, Jason; Singh, Abhyudai; Haibe-Kains, Benjamin; Khodadadi-Jamayran, Alireza; Neel, Benjamin G
Resistance to targeted therapies is an important clinical problem in HER2-positive (HER2+) breast cancer. "Drug-tolerant persisters" (DTPs), a sub-population of cancer cells that survive via reversible, non-genetic mechanisms, are implicated in resistance to tyrosine kinase inhibitors (TKIs) in other malignancies, but DTPs following HER2 TKI exposure have not been well characterized. We found that HER2 TKIs evoke DTPs with a luminal-like or a mesenchymal-like transcriptome. Lentiviral barcoding/single cell RNA-sequencing reveal that HER2+ breast cancer cells cycle stochastically through a "pre-DTP" state, characterized by a G0-like expression signature and enriched for diapause and/or senescence genes. Trajectory analysis/cell sorting show that pre-DTPs preferentially yield DTPs upon HER2 TKI exposure. Cells with similar transcriptomes are present in HER2+ breast tumors and are associated with poor TKI response. Finally, biochemical experiments indicate that luminal-like DTPs survive via estrogen receptor-dependent induction of SGK3, leading to rewiring of the PI3K/AKT/mTORC1 pathway to enable AKT-independent mTORC1 activation.
PMID: 34911733
ISSN: 2159-8290
CID: 5085072

Pan-ERBB kinase inhibition augments CDK4/6 inhibitor efficacy in oesophageal squamous cell carcinoma

Zhou, Jin; Wu, Zhong; Zhang, Zhouwei; Goss, Louisa; McFarland, James; Nagaraja, Ankur; Xie, Yingtian; Gu, Shengqing; Peng, Ke; Zeng, Yong; Zhang, Xiaoyang; Long, Henry; Nakagawa, Hiroshi; Rustgi, Anil; Diehl, J Alan; Meyerson, Matthew; Wong, Kwok-Kin; Bass, Adam
OBJECTIVE:Oesophageal squamous cell carcinoma (OSCC), like other squamous carcinomas, harbour highly recurrent cell cycle pathway alterations, especially hyperactivation of the CCND1/CDK4/6 axis, raising the potential for use of existing CDK4/6 inhibitors in these cancers. Although CDK4/6 inhibition has shown striking success when combined with endocrine therapy in oestrogen receptor positive breast cancer, CDK4/6 inhibitor palbociclib monotherapy has not revealed evidence of efficacy to date in OSCC clinical studies. Herein, we sought to elucidate the identification of key dependencies in OSCC as a foundation for the selection of targets whose blockade could be combined with CDK4/6 inhibition. DESIGN/METHODS:We combined large-scale genomic dependency and pharmaceutical screening datasets with preclinical cell line models, to identified potential combination therapies in squamous cell cancer. RESULTS:We identified sensitivity to inhibitors to the ERBB family of receptor kinases, results clearly extending beyond the previously described minority of tumours with EGFR amplification/dependence, specifically finding a subset of OSCCs with dual dependence on ERBB3 and ERBB2. Subsequently. we demonstrated marked efficacy of combined pan-ERBB and CDK4/6 inhibition in vitro and in vivo. Furthermore, we demonstrated that squamous lineage transcription factor KLF5 facilitated activation of ERBBs in OSCC. CONCLUSION/CONCLUSIONS:These results provide clear rationale for development of combined ERBB and CDK4/6 inhibition in these cancers and raises the potential for KLF5 expression as a candidate biomarker to guide the use of these agents. These data suggested that by combining existing Food and Drug Administration (FDA)-approved agents, we have the capacity to improve therapy for OSCC and other squamous cancer.
PMID: 33789967
ISSN: 1468-3288
CID: 5148152

Loss of TSC1/TSC2 sensitizes immune checkpoint blockade in non-small cell lung cancer

Huang, Qingyuan; Li, Fei; Hu, Hai; Fang, Zhaoyuan; Gao, Zhendong; Xia, Guozhan; Ng, Wai-Lung; Khodadadi-Jamayran, Alireza; Chen, Ting; Deng, Jiehui; Zhang, Hua; Almonte, Christina; Labbe, Kristen; Han, Han; Geng, Ke; Tang, Sittinon; Freeman, Gordon J; Li, Yuan; Chen, Haiquan; Wong, Kwok-Kin
Tuberous sclerosis complex subunit 1 (TSC1) and 2 (TSC2) are frequently mutated in non-small cell lung cancer (NSCLC), however, their effects on antitumor immunity remained unexplored. A CRISPR screening in murine KrasG12D
PMID: 35119931
ISSN: 2375-2548
CID: 5150752

Combined Inhibition of SHP2 and CXCR1/2 Promotes Anti-Tumor T Cell Response in NSCLC

Tang, Kwan Ho; Li, Shuai; Khodadadi-Jamayran, Alireza; Jen, Jayu; Han, Han; Guidry, Kayla; Chen, Ting; Hao, Yuan; Fedele, Carmine; Zebala, John A; Maeda, Dean Y; Christensen, James G; Olson, Peter; Athanas, Argus; Loomis, Cynthia A; Tsirigos, Aristotelis; Wong, Kwok-Kin; Neel, Benjamin G
SHP2 inhibitors (SHP2i) alone and in various combinations are being tested in multiple tumors with over-activation of the RAS/ERK pathway. SHP2 plays critical roles in normal cell signaling; hence, SHP2is could influence the tumor microenvironment. We found that SHP2i treatment depleted alveolar and M2-like macrophages, induced tumor-intrinsic CCL5/CXCL10 secretion and promoted B and T lymphocyte infiltration in Kras- and Egfr-mutant non-small cell lung cancer (NSCLC). However, treatment also increased intratumor gMDSCs via tumor-intrinsic, NF-kB-dependent production of CXCR2 ligands. Other RAS/ERK pathway inhibitors also induced CXCR2 ligands and gMDSC influx in mice, and CXCR2 ligands were induced in tumors from patients on KRASG12C-inhibitor trials. Combined SHP2(SHP099)/CXCR1/2(SX682) inhibition depleted a specific cluster of S100a8/9high gMDSCs, generated Klrg1+ CD8+ effector T cells with a strong cytotoxic phenotype but expressing the checkpoint receptor NKG2A, and enhanced survival in Kras- and Egfr-mutant models. Our results argue for testing RAS/ERK pathway/CXCR1/2/NKG2A inhibitor combinations in NSCLC patients.
PMID: 34353854
ISSN: 2159-8290
CID: 4969352

Cellular Origins of EGFR-Driven Lung Cancer Cells Determine Sensitivity to Therapy

Chen, Fan; Liu, Jinpeng; Flight, Robert M; Naughton, Kassandra J; Lukyanchuk, Alexsandr; Edgin, Abigail R; Song, Xiulong; Zhang, Haikuo; Wong, Kwok-Kin; Moseley, Hunter N B; Wang, Chi; Brainson, Christine F
Targeting the epidermal growth factor receptor (EGFR) with tyrosine kinase inhibitors (TKIs) is one of the major precision medicine treatment options for lung adenocarcinoma. Due to common development of drug resistance to first- and second-generation TKIs, third-generation inhibitors, including osimertinib and rociletinib, have been developed. A model of EGFR-driven lung cancer and a method to develop tumors of distinct epigenetic states through 3D organotypic cultures are described here. It is discovered that activation of the EGFR T790M/L858R mutation in lung epithelial cells can drive lung cancers with alveolar or bronchiolar features, which can originate from alveolar type 2 (AT2) cells or bronchioalveolar stem cells, but not basal cells or club cells of the trachea. It is also demonstrated that these clones are able to retain their epigenetic differences through passaging orthotopically in mice and crucially that they have distinct drug vulnerabilities. This work serves as a blueprint for exploring how epigenetics can be used to stratify patients for precision medicine decisions.
PMCID:8596110
PMID: 34622577
ISSN: 2198-3844
CID: 5067832

Targeting the Atf7ip-Setdb1 Complex Augments Antitumor Immunity by Boosting Tumor Immunogenicity

Hu, Hai; Khodadadi-Jamayran, Alireza; Dolgalev, Igor; Cho, Hyunwoo; Badri, Sana; Chiriboga, Luis A; Zeck, Briana; Lopez De Rodas Gregorio, Miguel; Dowling, Catríona M; Labbe, Kristen; Deng, Jiehui; Chen, Ting; Zhang, Hua; Zappile, Paul; Chen, Ze; Ueberheide, Beatrix; Karatza, Angeliki; Han, Han; Ranieri, Michela; Tang, Sittinon; Jour, George; Osman, Iman; Sucker, Antje; Schadendorf, Dirk; Tsirigos, Aristotelis; Schalper, Kurt A; Velcheti, Vamsidhar; Huang, Hsin-Yi; Jin, Yujuan; Ji, Hongbin; Poirier, John T; Li, Fei; Wong, Kwok-Kin
Substantial progress has been made in understanding how tumors escape immune surveillance. However, few measures to counteract tumor immune evasion have been developed. Suppression of tumor antigen expression is a common adaptive mechanism that cancers use to evade detection and destruction by the immune system. Epigenetic modifications play a critical role in various aspects of immune invasion, including the regulation of tumor antigen expression. To identify epigenetic regulators of tumor antigen expression, we established a transplantable syngeneic tumor model of immune escape with silenced antigen expression and used this system as a platform for a CRISPR-Cas9 suppressor screen for genes encoding epigenetic modifiers. We found that disruption of the genes encoding either of the chromatin modifiers activating transcription factor 7-interacting protein (Atf7ip) or its interacting partner SET domain bifurcated histone lysine methyltransferase 1 (Setdb1) in tumor cells restored tumor antigen expression. This resulted in augmented tumor immunogenicity concomitant with elevated endogenous retroviral (ERV) antigens and mRNA intron retention. ERV disinhibition was associated with a robust type I interferon response and increased T-cell infiltration, leading to rejection of cells lacking intact Atf7ip or Setdb1. ATF7IP or SETDB1 expression inversely correlated with antigen processing and presentation pathways, interferon signaling, and T-cell infiltration and cytotoxicity in human cancers. Our results provide a rationale for targeting Atf7ip or Setdb1 in cancer immunotherapy.
PMID: 34462284
ISSN: 2326-6074
CID: 5061142

A novel EGFR inhibitor suppresses survivin expression and tumor growth in human gefitinib-resistant EGFR-wild type and -T790M non-small cell lung cancer

Wang, Su-Pei; Hsu, Ya-Ping; Chang, Chien-Jen; Chan, Yu-Chi; Chen, Chien-Hung; Wang, Rou-Hsin; Liu, Kuang-Kai; Pan, Pei-Ying; Wu, Ya-Hui; Yang, Chih-Man; Chen, Chinpiao; Yang, Jinn-Moon; Liang, Mei-Chih; Wong, Kwok-Kin; Chao, Jui-I
Tyrosine kinase inhibitors of epidermal growth factor receptor (EGFR-TKIs) are currently used therapy for non-small cell lung cancer (NSCLC) patients; however, drug resistance during cancer treatment is a critical problem. Survivin is an anti-apoptosis protein, which promotes cell proliferation and tumor growth that highly expressed in various human cancers. Here, we show a novel synthetic compound derived from gefitinib, do-decyl-4-(4-(3-(4-(3-chloro-4-fluorophenylamino)-7-methoxyquinazolin-6-yloxy)propyl) piper-azin-1-yl)-4-oxobutanoate, which is named as SP101 that inhibits survivin expression and tumor growth in both the EGFR-wild type and -T790M of NSCLC. SP101 blocked EGFR kinase activity and induced apoptosis in the A549 (EGFR-wild type) and H1975 (EGFR-T790M) lung cancer cells. SP101 reduced survivin proteins and increased active caspase 3 for inducing apoptosis. Ectopic expression of survivin by a survivin-expressed vector attenuated the SP101-induced cell death in lung cancer cells. Moreover, SP101 inhibited the gefitinib-resistant tumor growth in the xenograft human H1975 lung tumors of nude mice. SP101 substantially reduced survivin proteins but conversely elicited active caspase 3 proteins in tumor tissues. Besides, SP101 exerted anticancer abilities in the gefitinib resistant cancer cells separated from pleural effusion of a clinical lung cancer patient. Consistently, SP101 decreased the survivin proteins and the patient-derived xenografted lung tumor growth in nude mice. Anti-tumor ability of SP101 was also confirmed in the murine lung cancer model harboring EGFR T790M-L858R. Together, SP101 is a new EGFR inhibitor with inhibiting survivin that can be developed for treating EGFR wild-type and EGFR-mutational gefitinib-resistance in human lung cancers.
PMID: 34597670
ISSN: 1873-2968
CID: 5106642

Targeting HER2 Exon 20 Insertion-Mutant Lung Adenocarcinoma with a Novel Tyrosine Kinase Inhibitor Mobocertinib

Han, Han; Li, Shuai; Chen, Ting; Fitzgerald, Michael; Liu, Shengwu; Peng, Chengwei; Tang, Kwan Ho; Cao, Shougen; Chouitar, Johara; Wu, Jiansheng; Peng, David; Deng, Jiehui; Gao, Zhendong; Baker, Theresa E; Li, Fei; Zhang, Hua; Pan, Yuanwang; Ding, Hailin; Hu, Hai; Pyon, Val; Thakurdin, Cassandra; Papadopoulos, Eleni; Tang, Sittinon; Gonzalvez, Francois; Chen, Haiquan; Rivera, Victor M; Brake, Rachael; Vincent, Sylvie; Wong, Kwok-Kin
No targeted treatments are currently approved for HER2 exon 20 insertion-mutant lung adenocarcinoma patients. Mobocertinib (TAK-788) is a potent irreversible tyrosine kinase inhibitor (TKI) designed to target human epidermal growth factor receptor 2 (HER2/ERBB2) exon 20 insertion mutations. However, the function of mobocertinib on HER2 exon 20 insertion-mutant lung cancer is still unclear. Here we conducted systematic characterization of preclinical models to understand the activity profile of mobocertinib against HER2 exon 20 insertions. In HER2 exon 20 insertion-mutant cell lines, the IC50 of mobocertinib was higher than poziotinib and comparable with or slightly lower than afatinib, neratinib, and pyrotinib. Mobocertinib had the lowest HER2 exon 20 insertion IC50/wild-type (WT) EGFR IC50 ratio, indicating that mobocertinib displayed the best selectivity profile in these models. Also, mobocertinib showed strong inhibitory activity in HER2 exon 20YVMA allograft and patient-derived xenograft models. In genetically engineered mouse models, HER2 exon 20G776>VC lung tumors exhibited a sustained complete response to mobocertinib, whereas HER2 exon 20YVMA tumors showed only partial and transient response. Combined treatment with a second antibody-drug conjugate (ADC) against HER2, ado-trastuzumab emtansine (T-DM1), synergized with mobocertinib in HER2 exon 20YVMA tumors. In addition to the tumor cell autonomous effect, sustained tumor growth control derived from M1 macrophage infiltration and CD4+ T-cell activation. These findings support the ongoing clinical development of mobocertinib (NCT02716116) and provide a rationale for future clinical evaluation of T-DM1 combinational therapy in HER2 exon 20YVMA insertion-mutant lung adenocarcinoma patients. SIGNIFICANCE: This study elucidates the potent inhibitory activity of mobocertinib against HER2 exon 20 insertion-mutant lung cancer and the synergic effect of combined mobocertinib and T-DM1, providing a strong rationale for clinical investigation.
PMCID:8530969
PMID: 34380634
ISSN: 1538-7445
CID: 5060992

Targeting HSPA1A in ARID2-deficient lung adenocarcinoma

Wang, Xue; Wang, Yuetong; Fang, Zhaoyuan; Wang, Hua; Zhang, Jian; Zhang, Longfu; Huang, Hsinyi; Jiang, Zhonglin; Jin, Yujuan; Han, Xiangkun; Hou, Shenda; Zhou, Bin; Meng, Feilong; Chen, Luonan; Wong, Kwok-Kin; Liu, Jinfeng; Zhang, Zhiqi; Zhang, Xin; Chen, Haiquan; Sun, Yihua; Hu, Liang; Ji, Hongbin
Somatic mutations of the chromatin remodeling gene ARID2 are observed in ∼7% of human lung adenocarcinomas (LUADs). However, the role of ARID2 in the pathogenesis of LUADs remains largely unknown. Here we find that ARID2 expression is decreased during the malignant progression of both human and mice LUADs. Using two KrasG12D
PMCID:8566174
PMID: 34858604
ISSN: 2053-714x
CID: 5065872