Article
Oncology
Qiong Qin, Xiaoqing Li, Xingmei Liang, Lili Zeng, Jing Wang, Linlin Sun, Diansheng Zhong
Summary: The study found that Snail plays a crucial role in the resistance mechanism of osimertinib, and downregulating Snail may reverse the resistance.
Article
Pharmacology & Pharmacy
Yuhong Jiang, Xin Zhuo, Xiujuan Fu, Yue Wu, Canquan Mao
Summary: This study revealed that PAR2 actively participates in gefitinib resistance in NSCLC. Inhibition of PAR2 enhanced gefitinib's effects on cell viability, migration, and apoptosis in both sensitive and resistant cells, indicating its potential in reversing gefitinib resistance. Additionally, the study found that the combination of a PAR2 inhibitor and gefitinib blocked ERK phosphorylation and epithelial-mesenchymal transition (EMT) more effectively than gefitinib alone, suggesting a new direction for overcoming drug resistance in NSCLC.
FRONTIERS IN PHARMACOLOGY
(2021)
Article
Pharmacology & Pharmacy
Xueting Cai, Jing Miao, Rongwei Sun, Sainan Wang, Miguel Angel Molina-Vila, Imane Chaib, Rafael Rosell, Peng Cao
Summary: Osimertinib-resistant EGFR-mutant NSCLC cell lines showed increased heme levels, while plasma heme levels were also elevated in patients treated with osimertinib. The antimalarial drug DHA was found to reverse osimertinib resistance by enhancing ROS levels and impairing heme metabolism. Combination treatment of osimertinib and DHA inhibited tumor growth and downregulated RTKs in a xenograft mouse model.
PHARMACOLOGICAL RESEARCH
(2021)
Article
Oncology
Sangah Lee, Jiyae Jung, Yu-Jin Lee, Seon-Kyu Kim, Jung-Ae Kim, Bo-Kyung Kim, Kyung Chan Park, Byoung-Mog Kwon, Dong Cho Han
Summary: The study identified HSF1 as a potential target protein to overcome EGFR-TKI resistance in NSCLC, demonstrating the efficacy of HSF1 inhibition in vitro and in vivo. This suggests a targetable HSF1 pathway to overcome multiple mechanisms of EGFR-TKI resistance.
Article
Cell Biology
Zhe Liu, Liang Ma, Yiming Sun, Wenying Yu, Xue Wang
Summary: The study demonstrated that the STAT3/ZEB1 axis is critical in gefitinib resistance in lung cancer, and a new potential therapeutic strategy targeting STAT3 has been identified with the inhibitor LL1. LL1 was shown to sensitize resistant cells to gefitinib by depleting STAT3 activity and blocking its signaling pathways, with little observed toxicity in animal models, indicating it could be a chemotherapeutic adjuvant for gefitinib resistance in NSCLC.
CELL DEATH & DISEASE
(2021)
Article
Pharmacology & Pharmacy
Geunho Choi, Daegeun Kim, Junehwan Oh
Summary: This study utilized artificial intelligence to discover potential drugs that can overcome acquired resistance in lung cancer patients, reducing the limitations of the current drug discovery process.
FRONTIERS IN PHARMACOLOGY
(2021)
Article
Biology
Xiaolong Tang, Lizhi Cheng, Guo Li, Yong-Ming Yan, Fengting Su, Dan-Ling Huang, Shuping Zhang, Zuojun Liu, Minxian Qian, Ji Li, Yong-Xian Cheng, Baohua Liu
Summary: The small molecule compound D6 demonstrates promising efficacy in treating EGFR-TKI resistant NSCLC by targeting the protein-protein interaction between HSP90 and T790M-EGFR, offering a potential alternative strategy to overcome drug resistance.
COMMUNICATIONS BIOLOGY
(2021)
Review
Oncology
Dan Yan, H. Shelton Earp, Deborah DeRyckere, Douglas K. Graham
Summary: MERTK and AXL are abnormally expressed in the majority of NSCLCs, providing a survival advantage for cells and correlating with metastasis, drug resistance, and disease progression. Host tumor infiltrating cells' TAM receptors also play crucial roles in the immunosuppressive tumor microenvironment. These factors make MERTK and AXL attractive targets for NSCLC treatment.
Article
Medicine, Research & Experimental
Dan Yan, Justus M. Huelse, Dmitri Kireev, Zikang Tan, Luxiao Chen, Subir Goyal, Xiaodong Wang, Stephen Frye, Madhusmita Behera, Frank Schneider, Suresh S. Ramalingam, Taofeek Owonikoko, H. Shelton Earp, Deborah DeRyckere, Douglas K. Graham
Summary: Acquired resistance is inevitable in non-small cell lung cancers (NSCLCs) treated with osimertinib (OSI). Activation of MERTK is associated with OSI resistance and inhibition of MERTK kinase can resensitize resistant cells to OSI.
JOURNAL OF CLINICAL INVESTIGATION
(2022)
Article
Oncology
Chia-Chi Hsu, Albert Ying-Po Yang, Jui-Yi Chen, Hsin-Hui Tsai, Shu-Heng Lin, Pei-Chen Tai, Ming-Hung Huang, Wei-Hsun Hsu, Anya Maan-Yuh Lin, James Chih-Hsin Yang
Summary: EGFR mutations are common in NSCLC, especially in Asian populations, and are effectively treated with EGFR-TKIs, but resistance is a challenge. The study identified lysine as essential for EGFR-mutant NSCLC survival and resistance, reducing the required TKI dosage and enhancing therapeutic potential. This highlights lysine stress as a novel strategy to improve EGFR-mutant NSCLC therapy.
Article
Oncology
Anup Kumar Biswas, Seoyoung Han, Yifan Tai, Wanchao Ma, Courtney Coker, S. Aidan Quinn, Ahmad Rushdi Shakri, Timothy James Zhong, Hanna Scholze, Galina G. Lagos, Angeliki Mela, Katia Manova-Todorova, Elisa de Stanchina, Adolfo A. Ferrando, Cathy Mendelsohn, Peter Canoll, Helena A. Yu, Paul K. Paik, Anjali Saqi, Catherine A. Shu, Mark G. Kris, Joan Massague, Swarnali Acharyya
Summary: The high expression of intracellular S100A9 in cancer cells leads to brain metastasis relapse in patients with EGFR-mutant lung cancer treated with osimertinib. S100A9 promotes brain metastasis of osimertinib-resistant cancer cells by upregulating ALDH1A1 expression and activating the retinoic acid signaling pathway.
Article
Cell Biology
Jun Wang, Xi Liu, Yuanfeng Huang, Pan Li, Minqiang Yang, Shanshan Zeng, Danyang Chen, Qian Wang, Hao Liu, Kai Luo, Jin Deng
Summary: This study found that overexpression of NNMT is associated with acquired resistance to EGFR tyrosine kinase inhibitors (TKIs). Targeting NNMT may be a potential therapeutic strategy to overcome EGFR TKI resistance.
CELL DEATH DISCOVERY
(2022)
Article
Chemistry, Multidisciplinary
Xing-mei Liang, Qiong Qin, Bo-ning Liu, Xiao-qing Li, Li-li Zeng, Jing Wang, Ling-ping Kong, Dian-sheng Zhong, Lin-lin Sun
Summary: The study reveals that DNA damage repair capacity is compromised in osimertinib-resistant cells, and inhibiting DNA-PK can increase sensitivity to osimertinib. Combination of osimertinib with DNA-PK inhibitors synergistically suppresses proliferation of resistant cells.
ACTA PHARMACOLOGICA SINICA
(2021)
Review
Pharmacology & Pharmacy
Frank Aboubakar Nana, Sebahat Ocak
Summary: Osimertinib is now a standard first-line treatment for NSCLC with specific EGFR mutations, however, resistance mechanisms are inevitable. This study discusses acquired resistance mechanisms, specifically the BRAF V600 mutation, in EGFR-mutant NSCLC patients treated with Osimertinib in combination with dabrafenib and trametinib.
Article
Oncology
Philippe Giron, Carolien Eggermont, Amir Noeparast, Hugo Vandenplas, Erik Teugels, Ramses Forsyth, Olivier De Wever, Pedro Aza-Blanc, Gustavo J. Gutierrez, Jacques De Greve
Summary: The study identifies USP13 as a protein that can increase the sensitivity of lung cancer cells with EGFR mutations to targeted therapy, potentially improving treatment efficacy.
INTERNATIONAL JOURNAL OF CANCER
(2021)
Article
Oncology
Paul K. Paik, Pang-Dian Fan, Besnik Qeriqi, Azadeh Namakydoust, Bobby Daly, Linda Ahn, Rachel Kim, Andrew Plodkowski, Ai Ni, Jason Chang, Rachel Fanaroff, Marc Ladanyi, Elisa de Stanchina, Charles M. Rudin
Summary: Increased understanding of the mutational landscape of squamous cell lung cancers (LUSCs) has not resulted in effective targeted therapies. This study investigates the potential of TORC1/2 inhibitor TAK-228 in NSCLC models with NRF2-activating alterations and reports positive outcomes in a phase 2 clinical trial. TAK-228 shows promising single-agent activity in LUSC patients with NRF2 activation and highlights the importance of targeting metabolism in NSCLC.
JOURNAL OF THORACIC ONCOLOGY
(2023)
Review
Oncology
Kenta Kawasaki, Natasha Rekhtman, Alvaro Quintanal-Villalonga, Charles M. Rudin
Summary: The review provides a comprehensive overview of the current understanding of NENs in the gastrointestinal system and lung from both clinical and biological perspectives. The authors discuss the commonalities and organ-specific differences of NENs and advocate for a tissue-agnostic approach to drug development, in order to improve patient care by accelerating research across different disease entities.
NATURE REVIEWS CLINICAL ONCOLOGY
(2023)
Article
Endocrinology & Metabolism
Emerson E. Lee, Tanmay Singh, Chen Hu, Misop Han, Curtiland Deville, Aditya Halthore, Stephen Greco, Phuoc Tran, Theodore DeWeese, Daniel Y. Song
Summary: This study found that initiating salvage radiation therapy (SRT) when PSA levels are below 0.5 ng/ml is associated with improved metastasis-free survival (MFS) in patients with biochemical recurrence. Seminal vesicle invasion is also associated with shorter time to biochemical failure and eventual metastasis.
Article
Oncology
Phuoc T. Tran, Kathryn Lowe, Hua-Ling Tsai, Daniel Y. Song, Arthur Y. Hung, Jason W. D. Hearn, Steven Miller, James A. Proudfoot, Matthew P. Deek, Ryan Phillips, Tamara Lotan, Channing J. Paller, Catherine H. Marshall, Mark Markowski, Shirl Dipasquale, Samuel Denmeade, Michael Carducci, Mario Eisenberger, Theodore L. DeWeese, Matthew Orton, Curtiland Deville, Elai Davicioni, Stanley L. Liauw, Elisabeth I. Heath, Stephen Greco, Neil B. Desai, Daniel E. Spratt, Felix Feng, Hao Wang, Tomasz M. Beer, Emmanuel S. Antonarakis
Summary: This study aimed to investigate the effect of enzalutamide on freedom from PSA progression in men with recurrent prostate cancer after radical prostatectomy. The results showed that enzalutamide monotherapy for 6 months in combination with salvage radiation therapy delayed PSA progression and was safe for high-risk patients with postoperative recurrence.
JOURNAL OF CLINICAL ONCOLOGY
(2023)
Article
Oncology
Noura J. Choudhury, Antonio Marra, Jane S. Y. Sui, Jessica Flynn, Soo-Ryum Yang, Christina J. Falcon, Pier Selenica, Adam J. Schoenfeld, Natasha Rekhtman, Daniel Gomez, Michael F. Berger, Marc Ladanyi, Maria Arcila, Charles M. Rudin, Gregory J. Riely, Mark G. Kris, Glenn Heller, Jorge S. Reis-Filho, Helena A. Yu
Summary: The study explores the potential of identifying and intervening on molecular markers associated with therapeutic resistance to improve patient outcomes in metastatic EGFR-mutant lung cancer treated with first-line osimertinib. Baseline atypical EGFR and concurrent TP53/RB1 alterations are associated with shorter progression-free survival on first-line osimertinib. Tissue-based genomic analysis allows for treatment adaptation based on identified mechanisms of resistance at the time of progression, leading to improved postprogression survival.
JOURNAL OF THORACIC ONCOLOGY
(2023)
Article
Oncology
Jennifer Y. Sheng, Claire F. Snyder, Katherine C. Smith, Jennifer DeSanto, Nancy Mayonado, Susan Rall, Sharon White, Amanda L. Blackford, Fabian M. Johnston, Robert L. Joyner, Joan Mischtschuk, Kimberly S. Peairs, Elissa Thorner, Phuoc T. Tran, Antonio C. Wolff, Youngjee Choi
Summary: Survivorship care plans (SCPs) are important for communicating cancer-related information. This study found that some tests conducted after SCP receipt were not consistent with guidelines, indicating overuse. This analysis identifies areas for improvement in guideline-concordant care.
Article
Oncology
Charles M. Rudin, Hardev S. Pandha, Matthew Zibelman, Wallace L. Akerley, Kevin J. Harrington, Daphne Day, Andrew G. Hill, Steven J. O'Day, Timothy D. Clay, Gavin M. Wright, Ross R. Jennens, David E. Gerber, Jonathan E. Rosenberg, Christy Ralph, David C. Campbell, Brendan D. Curti, Jaime R. Merchan, Yixin Ren, Emmett Schmidt, Lisa Guttman, Sumati Gupta
Summary: This study evaluated the efficacy and safety of V937 combined with pembrolizumab in patients with advanced solid tumors. The results showed that the combination therapy had a manageable safety profile, but did not achieve greater efficacy than pembrolizumab monotherapy in non-small cell lung cancer and urothelial cancer.
JOURNAL FOR IMMUNOTHERAPY OF CANCER
(2023)
Editorial Material
Oncology
Salomon Tendler, Charles M. Rudin
JOURNAL OF CLINICAL ONCOLOGY
(2023)
Review
Oncology
Charles M. M. Rudin, Martin Reck, Melissa L. L. Johnson, Fiona Blackhall, Christine L. L. Hann, James Chih-Hsin Yang, Julie M. M. Bailis, Gwyn Bebb, Amanda Goldrick, John Umejiego, Luis Paz-Ares
Summary: Small cell lung cancer (SCLC) is a highly aggressive neuroendocrine carcinoma with limited treatment options. DLL3, a Notch inhibitory ligand, is overexpressed on SCLC cells, making it an attractive therapeutic target. This article discusses the clinical experience with a DLL3-targeting antibody-drug conjugate called Rova-T, as well as other DLL3-targeting agents currently in development, including T-cell engager molecules and CAR T-cell therapy. The challenges and opportunities for DLL3-targeting therapies, such as using DLL3 as a biomarker and exploring combinatorial approaches, are also discussed.
JOURNAL OF HEMATOLOGY & ONCOLOGY
(2023)
Article
Oncology
Charles M. Rudin, David Balli, W. Victoria Lai, Allison L. Richards, Evelyn Nguyen, Jacklynn Egger, Noura J. Choudhury, Triparna Sen, Andrew Chow, John T. Poirier, William J. Geese, Matthew D. Hellmann, Ann Forslund
Summary: A study found that antigen presentation machinery signature and infiltrating CD8 T cells were correlated with survival in SCLC patients treated with nivolumab, suggesting their potential as biomarkers for predicting immunotherapy efficacy. The study also identified the association between durable benefit from immunotherapy and antigen processing and presentation.
JOURNAL OF THORACIC ONCOLOGY
(2023)
Article
Immunology
Ariella Glasner, Samuel A. Rose, Roshan Sharma, Herman Gudjonson, Tinyi Chu, Jesse A. Green, Sham Rampersaud, Izabella K. Valdez, Emma S. Andretta, Bahawar S. Dhillon, Michail Schizas, Stanislav Dikiy, Alejandra Mendoza, Wei Hu, Zhong-Min Wang, Ojasvi Chaudhary, Tianhao Xu, Linas Mazutis, Gabrielle Rizzuto, Alvaro Quintanal-Villalonga, Parvathy Manoj, Elisa de Stanchina, Charles M. Rudin, Dana Pe'er, Alexander Y. Rudensky
Summary: Traditional roles of regulatory T (T-reg) cells as suppressors of antigen presenting cells and effector T cells have expanded to include tissue maintenance functions, suggesting a broader regulatory role than previously thought. In lung cancer and injury-induced inflammation, T-reg cell depletion led to changes in gene expression in fibroblasts, endothelial and myeloid cells, involving VEGF and CCR2 signaling. Combined T-reg cell depletion and short-term VEGF blockade showed improved control of PD-1 blockade-resistant lung adenocarcinoma progression, highlighting the potential of combination therapies for solid organ cancers.
Editorial Material
Oncology
Charles M. Rudin
Article
Oncology
Subhamoy Chakraborty, Charles Coleman, Parvathy Manoj, Deniz Demircioglu, Nisargbhai Shah, Elisa de Stanchina, Charles M. Rudin, Dan Hasson, Triparna Sen
Summary: Lurbinectedin significantly reduces cell viability in most SCLC models, with the best response observed in POU2F3-driven SCLC cells. We also found that lurbinectedin, either as a single agent or in combination with osimertinib, shows an appreciable antitumor response in EGFR-mutant lung adenocarcinoma models with histologic transformation to SCLC. Transcriptomic analysis revealed the induction of apoptosis, repression of epithelial-mesenchymal transition, and modulation of PI3K/AKT, NOTCH signaling associated with lurbinectedin response in both de novo and transformed SCLC models.
CLINICAL CANCER RESEARCH
(2023)
Article
Oncology
Joy A. Pai, Matthew D. Hellmann, Jennifer L. Sauter, Marissa Mattar, Hira Rizvi, Hyung Jun Woo, Nisargbhai Shah, Evelyn M. Nguyen, Fathema Z. Uddin, Alvaro Quintanal-Villalonga, Joseph M. Chan, Parvathy Manoj, Viola Allaj, Marina K. Baine, Umesh K. Bhanot, Mala Jain, Irina Linkov, Fanli Meng, David Brown, Jamie E. Chaft, Andrew J. Plodkowski, Mathieu Gigoux, Helen H. Won, Triparna Sen, Daniel K. Wells, Mark T. A. Donoghue, Elisa de Stanchina, Jedd D. Wolchok, Brian Loomis, Taha Merghoub, Charles M. Rudin, Andrew Chow, Ansuman T. Satpathy
Summary: Paired scRNA/TCR-seq analysis of T cells from NSCLC patients after ICB reveals clonally linked TFH and tumor-specific CD8+ T cells in tumor draining LNs. Exhausted CD8+ T cells, Treg, and TFH cells show progressive exhaustion trajectories with proximity to the tumor microenvironment. Longitudinal tracking demonstrates the persistence of tumor-specific T cell clones in peripheral blood for years after ICB therapy.
Article
Medicine, Research & Experimental
Janneke E. Jaspers, Jonathan F. Khan, William D. Godfrey, Andrea Lopez, Metamia Ciampricotti, Charles M. Rudin, Renier J. Brentjens
Summary: This study developed a chimeric antigen receptor (CAR) against DLL3 and demonstrated its antitumor efficacy in xenograft and murine SCLC models. CAR T cell expression of IL-18 enhanced the potency of DLL3-targeting CAR T cell therapy and increased the activation of CAR T cells and tumor-infiltrating lymphocytes. Human IL-18-secreting anti-DLL3 CAR T cells showed durable responses in multiple SCLC models, and this effect could be further enhanced with anti-PD-1 blockade.
JOURNAL OF CLINICAL INVESTIGATION
(2023)