Article
Oncology
Andrea Forschner, Tobias Sinnberg, Gabi Mroz, Christopher Schroeder, Christian Philipp Reinert, Sergios Gatidis, Michael Bitzer, Thomas Eigentler, Claus Garbe, Heike Niessner, Martin Rocken, Cristiana Roggia, Sorin Armeanu-Ebinger, Olaf Riess, Sven Mattern, Dominik Nann, Irina Bonzheim
Summary: Limited treatment options exist for metastatic NRAS mutant melanoma patients resistant to immune checkpoint inhibitors. Molecular defects in cell cycle regulation can be additional challenges for these patients. Individualized therapy based on next-generation sequencing results can be effective, and further collaborative research is needed to expand treatment options for NRAS mutated melanoma.
FRONTIERS IN ONCOLOGY
(2021)
Article
Oncology
Olivia Vidal-Cruchez, Victoria J. Nicolini, Tifenn Rete, Karine Jacquet, Roger Rezzonico, Caroline Lacoux, Marie-Angela Domdom, Barnabe Romeo, Jeremie Roux, Arnaud Hubstenberger, Bernard Mari, Baharia Mograbi, Paul Hofman, Patrick Brest
Summary: Cancer therapies targeting the MAPK pathway lead to drug resistance. Overexpression of RAS has been linked to this resistance, but the underlying mechanisms are unclear. This study shows that MEK inhibitors increase translation of KRAS and NRAS oncogenes through liquid-liquid phase separation, specifically P-body dissolution. This feedback loop involving P-bodies and phase separation could be important for future targeted therapies.
Article
Oncology
Craig M. Goodwin, Andrew M. Waters, Jennifer E. Klomp, Sehrish Javaid, Kirsten L. Bryant, Clint A. Stalnecker, Kristina Drizyte-Miller, Bjoern Papke, Runying Yang, Amber M. Amparo, Irem Ozkan-Dagliyan, Elisa Baldelli, Valerie Calvert, Mariaelena Pierobon, Jessica A. Sorrentino, Andrew P. Beelen, Natalie Bublitz, Mareen Luethen, Kris C. Wood, Emanuel F. Petricoin III, Christine Sers, Autumn J. McRee, Adrienne D. Cox, Channing J. Der
Summary: Mutation of CDKN2A and activation of KRAS are crucial for the development and malignant growth of PDAC. Combination treatment with CDK4/6 and ERK-MAPK inhibitors synergistically suppresses the growth of PDAC cells and organoids by blocking compensatory upregulation of signaling pathways. CRISPR-Cas9 screening and protein activity mapping uncover novel combinations that enhance the potency of CDK4/6 inhibitors and overcome drug-induced compensations in PDAC.
Article
Oncology
Martin Salzmann, Johannes Pawlowski, Carmen Loquai, David A. Rafei-Shamsabadi, Frank Meiss, Selma Ugurel, Dirk Schadendorf, Friedegund Meier, Alexander H. Enk, Jessica C. Hassel
Summary: This retrospective, multi-centre study evaluated the clinical course of patients with advanced NRAS-mutated melanoma treated with MEK inhibitors (MEKi) in German cancer centres. The results showed that MEKi can stabilize the disease course but expectations regarding ongoing tumor response should be tempered.
EUROPEAN JOURNAL OF CANCER
(2022)
Article
Endocrinology & Metabolism
Jaime M. Pita, Eric Raspe, Katia Coulonval, Myriam Decaussin-Petrucci, Maxime Tarabichi, Genevieve Dom, Frederick Libert, Ligia Craciun, Guy Andry, Laurence Wicquart, Emmanuelle Leteurtre, Christophe Tresallet, Laura A. Marlow, John A. Copland, Cosimo Durante, Carine Maenhaut, Branca M. Cavaco, Jacques E. Dumont, Giuseppe Costante, Pierre P. Roger
Summary: CDK4/6 inhibitors have shown effectiveness in treating advanced thyroid cancers, especially poorly differentiated and anaplastic thyroid carcinomas. The phosphorylation of CDK4 at T172 is crucial for its activity and sensitivity to CDK4/6 inhibitors.
FRONTIERS IN ENDOCRINOLOGY
(2023)
Article
Oncology
Alexey V. Sorokin, Preeti Kanikarla Marie, Lea Bitner, Muddassir Syed, Melanie Woods, Ganiraju Manyam, Lawrence N. Kwong, Benny Johnson, Van K. Morris, Philip Jones, David G. Menter, Michael S. Lee, Scott Kopetz
Summary: This study evaluates the therapeutic efficacy and safety of combined MEK-CDK4/6 inhibition in RAS mutant colorectal cancer using patient-derived xenografts and clinical trials, identifies biomarkers of response, and uncovers targetable mechanisms of resistance.
Article
Biochemistry & Molecular Biology
Jiating Qi, Zhuqing Ouyang
Summary: This article summarizes the targeted therapies for cyclin-dependent kinase 4/6 (CDK4/6), including CRISPR, siRNA, and drug inhibition. It highlights the mechanisms of small molecular inhibitors and drug resistance, and describes strategies to combat resistance.
Review
Biochemistry & Molecular Biology
Ellen Voigt, Dawn E. Quelle
Summary: This review focuses on the oncogenic transcription factor FOXM1 in malignant peripheral nerve sheath tumors (MPNSTs) and discusses its role in the disease. The authors suggest that FOXM1, along with MEK and CDK4/6, could be new clinically relevant targets for MPNST therapy.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Oncology
Jiayuecheng Pang, Hengyu Li, Yuan Sheng
Summary: This study summarizes and visualizes the current research direction and development trend of CDK4/6 inhibitor resistance. The main research efforts in this field are currently focused on Palbociclib and Abemaciclib, as well as the mechanisms of drug resistance and post-drug resistance therapies involving MEK inhibitors, PI3K-AKT-MTOR pathways or inhibitors, EGFR-related pathways, EGFR inhibitors, TKI inhibitors, MAPK pathways, etc.
FRONTIERS IN ONCOLOGY
(2022)
Review
Chemistry, Medicinal
Denisa Hendrychova, Radek Jorda, Vladimir Krystof
Summary: Pharmacological inhibition of CDK4/6 has shown promising results in treating breast cancer and other cancers, with complex cellular responses and multiple mechanisms involved. It is crucial to comprehensively characterize the selectivity profiles of these inhibitors for maximizing clinical efficacy and safety, as well as for potential repurposing in treating additional diseases.
MEDICINAL RESEARCH REVIEWS
(2021)
Article
Oncology
Ming Zhao, Stephen Scott, Kurt W. Evans, Erkan Yuca, Turcin Saridogan, Xiaofeng Zheng, Heping Wang, Anil Korkut, Christian X. Cruz Pico, Mehmet Demirhan, Bryce Kirby, Scott Kopetz, Irmina Diala, Alshad S. Lalani, Sarina Piha-Paul, Funda Meric-Bernstam
Summary: In this preclinical study, neratinib showed synergistic effects with multiple agents in HER2(+) breast cancer cells, and combination with CDK4/6, mTOR, and MEK inhibitors demonstrated significant efficacy in patient-derived xenograft models. These findings provide strong preclinical evidence for the combination therapy of neratinib with CDK4/6, mTOR, and MEK inhibitors for HER2(+) cancer treatment.
CLINICAL CANCER RESEARCH
(2021)
Article
Oncology
Peter Kar Han Lau, Carleen Cullinane, Susan Jackson, Rachael Walker, Lorey K. Smith, Alison Slater, Laura Kirby, Riyaben P. Patel, Bianca von Scheidt, Clare Y. Slaney, Grant A. McArthur, Karen E. Sheppard
Summary: The combination of adoptive cell transfer (ACT) with BRAF-MEK and CDK4/6 inhibitors has shown to be highly efficacious against BRAF(V600) melanoma, providing prolonged and deep anti-tumor responses. This study offers additional pre-clinical evidence to support the combination of BRAF-MEK-CDK4/6 inhibitors and ACT in clinical trials.
Article
Pharmacology & Pharmacy
Qian Zhao, Teng Wang, Huanhuan Wang, Cheng Cui, Wen Zhong, Diyi Fu, Wanlin Xi, Lu Si, Jun Guo, Ying Cheng, Hongqi Tian, Pei Hu
Summary: This study investigated the pharmacokinetics of tunlametinib and its main metabolite M8 in patients with NRAS-mutant melanoma. The results showed that tunlametinib was rapidly absorbed and eliminated at a medium speed after drug withdrawal. There was a general dose-proportional increase in pharmacokinetic body exposure. Slight accumulation was found after multiple oral doses. The findings provide guidance for the dosing regimen of tunlametinib.
FRONTIERS IN PHARMACOLOGY
(2022)
Article
Oncology
Masahiro Ohara, Kengo Saito, Ken Kageyama, Mizue Terai, Hanyin Cheng, Andrew E. Aplin, Takami Sato
Summary: Uveal melanoma (UM) is a common eye cancer in adults, with up to 50% of patients developing metastases. A preclinical study showed that combining CDK4/6 inhibitor with cMET inhibitor could provide significant clinical benefit to patients with metastatic uveal melanoma by suppressing tumor growth.
Article
Multidisciplinary Sciences
Gonzalo L. Gonzalez-Del Pino, Kunhua Li, Eunyoung Park, Anna M. Schmoker, Byung Hak Ha, Michael J. Eck
Summary: The dysregulation of the RAF/MEK/ERK pathway is associated with many cancers, making the proteins involved, like MEK, a focus of drug discovery efforts. Allosteric MEK inhibitors have complex effects on this pathway and are used in combination with BRAF inhibitors in malignant melanoma. Recent studies suggest that these inhibitors act most potently on BRAF/MEK complexes rather than on free active MEK.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2021)
Meeting Abstract
Oncology
J. Randolph Randolph Hecht, Scott Kopetz, Sandip Pravin Patel, Theodore Welling, Maria Pia Morelli, Mitesh J. Borad, Julian R. Molina, Kedar Kirtane, Yi Lin, Michelle Fan-Port, Armen Mardiros, Karl Beutner, Ariane Lozac'hmeur, Denise Lau, Kirstin B. Liechty, Judy Vong, Eric Ng, David G. Maloney, William Y. Go, Diane M. Simeone
JOURNAL OF CLINICAL ONCOLOGY
(2022)
Meeting Abstract
Oncology
Scott Kopetz, Takayuki Yoshino, Tae Won Kim, Jayesh Desai, Rona Yaeger, Eric Van Cutsem, Fortunato Ciardiello, Harpreet Singh Wasan, Tim Maughan, Yuanyuan Zhang, Tiziana Usari, Chin-Hee Chung, Xiaosong Zhang, Josep Tabernero
JOURNAL OF CLINICAL ONCOLOGY
(2022)
Meeting Abstract
Oncology
Benny Johnson, Dong Yang, Hiba I. Dada, Leylah Drusbosky, Scott Kopetz
JOURNAL OF CLINICAL ONCOLOGY
(2022)
Meeting Abstract
Oncology
Oscar Villarreal, Fadl A. Zeineddine, Ray Chacko, Christine Megerdichian Parseghian, Benny Johnson, Jason Willis, Michael Sangmin Lee, Van K. Morris, Arvind Dasari, Kanwal Pratap Singh Raghav, Michael J. Overman, Y. Nancy You, Yinghong Wang, Dipen M. Maru, John Paul Y. C. Shen, Scott Kopetz
JOURNAL OF CLINICAL ONCOLOGY
(2022)
Meeting Abstract
Oncology
Arvind Dasari, Yan Lin, Scott Kopetz, Samuel A. Jacobs, Peter C. Lucas, Ibrahim Halil Halil Sahin, Dustin A. Deming, Agop Philip Philip, Theodore S. Hong, Norman Wolmark, Greg Yothers, Thomas J. George, Christopher Hanyoung Lieu
JOURNAL OF CLINICAL ONCOLOGY
(2022)
Article
Mathematical & Computational Biology
Rongji Mu, Jin Xu, Rui (Sammi) Tang, Scott Kopetz, Ying Yuan
Summary: A new approach is proposed to combine targeted or immunotherapy with standard care to treat different cancers. This method uses a master protocol and Bayesian modeling to evaluate combination therapies across multiple indications in a more efficient manner.
STATISTICS IN MEDICINE
(2022)
Article
Multidisciplinary Sciences
Seyed Pairawan, Argun Akcakanat, Scott Kopetz, Coya Tapia, Xiaofeng Zheng, Huiqin Chen, Min Jin Ha, Yasmeen Rizvi, Vijaykumar Holla, Jing Wang, Kurt W. Evans, Ming Zhao, Naifa Busaidy, Bingliang Fang, Jack A. Roth, Ecaterina Ileana Dumbrava, Funda Meric-Bernstam
Summary: Combination therapy with MEK inhibitor selumetinib and MDM2 inhibitor KRT-232 was evaluated in colon and thyroid cancer models. The study showed that the combination therapy had better antitumor efficacy than single drug therapy in both in vitro and in vivo settings.
SCIENTIFIC REPORTS
(2022)
Letter
Oncology
Sajid Khan, Janet Wiegand, Peiyi Zhang, Wanyi Hu, Dinesh Thummuri, Vivekananda Budamagunta, Nan Hua, Lingtao Jin, Carmen J. Allegra, Scott E. Kopetz, Maria Zajac-Kaye, Frederic J. Kaye, Guangrong Zheng, Daohong Zhou
Summary: KRAS(G12C) mutation is associated with tumor identification and its sensitivity to current treatments. This study demonstrates the synergistic effect of sotorasib and DT2216 combination therapy on certain KRAS(G12C) tumor cell lines, leading to enhanced efficacy in treating these tumors.
JOURNAL OF HEMATOLOGY & ONCOLOGY
(2022)
Article
Oncology
Marwan Fakih, Huakang Tu, Hil Hsu, Shivani Aggarwal, Emily Chan, Marko Rehn, Victoria Chia, Scott Kopetz
Summary: This article describes clinicopathologic characteristics, treatment patterns, overall survival, and real-world progression-free survival in patients with metastatic colorectal cancer and specific KRAS mutations. The results show that patients with the KRAS p.G12C mutation have poor treatment outcomes and potential prognostic implications.
Article
Oncology
Van Morris, Bryan Kee, Michael Overman, Arvind Dasari, Kanwal Raghav, Benny Johnson, Christine Parseghian, Robert A. Wolff, Naveen Garg, Cathy Eng, Scott Kopetz
Summary: The study analyzed the characteristics and survival rates of patients with BRAF(V60)(0E) mutated metastatic CRC, finding significant differences in clinical/pathologic features between patients with favorable and poor outcomes, including hepatic involvement, metachronous metastases, and treatment modalities. While the overall prognosis for most patients with BRAF(V60)(0E) mutated metastatic CRC remains poor, a small subset may achieve exceptionally favorable long-term survival.
JOURNAL OF GASTROINTESTINAL ONCOLOGY
(2022)
Article
Oncology
Kanwal Raghav, Fang-Shu Ou, Alan P. Venook, Federico Innocenti, Ryan Sun, Heinz-Josef Lenz, Scott Kopetz
Summary: Clinical trial updates allow for dissemination of additional results from studies where the primary end point has already been reported. This study aimed to determine the prevalence of acquired genomic alterations (Acq-GAs) on anti-EGFR-chemotherapy compared to anti-VEGF-chemotherapy and later-line anti-EGFR-antibody therapy in metastatic colorectal cancer (mCRC). The findings indicate divergent resistance mechanisms with rare occurrence of Acq-GAs with up-front use of anti-EGFR-chemotherapy.
JOURNAL OF CLINICAL ONCOLOGY
(2023)
Editorial Material
Oncology
Veronika Fedirko, Scott Kopetz, Carrie R. Daniel
JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE
(2023)
Editorial Material
Oncology
Madhulika Eluri, Scott Kopetz, Christine M. Parseghian
Summary: The use of serial ctDNA in metastatic colorectal cancer has the potential to refine patient selection, reduce chemotherapy toxicity, and assess emerging resistance mechanisms for novel therapeutic strategies. However, important questions remain regarding its validation as a predictive biomarker of treatment response.
CLINICAL CANCER RESEARCH
(2023)
Letter
Oncology
Kanwal Raghav, Scott Kopetz, Ying Yuan
JOURNAL OF CLINICAL ONCOLOGY
(2023)
Article
Oncology
Blessie Elizabeth Nelson, Apostolia M. Tsimberidou, Xueyao Fu, Siqing Fu, Vivek Subbiah, Anil K. Sood, Jordi Rodon, Daniel D. Karp, George Blumenschein, Scott Kopetz, Shubham Pant, Sarina A. Piha-Paul
Summary: This study evaluated the combination of bevacizumab, temsirolimus, and valproic acid in patients with advanced malignancies and found modest efficacy but significant toxicity. The study is the first to evaluate this combination and suggests potential for anticancer activity, but careful management of toxicity is necessary for future development.