Wang-Gillam, Andrea
Mayo Clinic
Division of Medical Oncology, Department of Internal Medicine, Washington University in St. Louis, St. Louis, MO 63110, USA.
Citations 2
Defining the KRAS- and ERK-dependent transcriptome in KRAS-mutant cancers
Klomp, Jennifer E. , Stalnecker, Clint A. , Bryant, Kirsten L. , Edwards, A. Cole , Drizyte‐Miller, Kristina , Hibshman, Priya S. , Diehl, J. Nathaniel , Lee, Ye S. , Morales, Alexis Jean , Taylor, Khalilah E. , Peng, Sen, Tran, Nhan L. , Prevatte, Alex W., Hover, Laura D. , Hallin, Jill , Chowdhury, Saikat , Coker, Oluwadara , Olson, Peter , Christensen, James G. , Graves, Lee M. , Wennerberg, Krister , Klomp, Jeffrey A , Klomp, Jennifer E , Stalnecker, Clint A , Bryant, Kirsten L , Drizyte-Miller, Kristina , Diehl, J Nathaniel , Lee, Ye S , Morales, Alexis J , Taylor, Khalilah E , Herring, Laura E , Barker, Natalie K , Hallin, Jill , Chowdhury, Saikat , Coker, Oluwadara , Lee, Hey Min , Goodwin, Craig M , Gautam, Prson , Olson, Peter , Christensen, James G , Shen, John P , Kopetz, Scott , Graves, Lee M , Lim, Kian-Huat , Wang-Gillam, Andrea , Wennerberg, Krister , Cox, Adrienne D , Der, Channing J , Tran, Nhan L , Herring, Laura E. , Barker, Natalie K. , Gautam, Prson , Kopetz, Scott , Wang‐Gillam, Andrea , Cox, Adrienne D.
Science | June 6, 2024 | Volume: 384 | Issue: 6700 | Pages: No page available
How the KRAS oncogene drives cancer growth remains poorly understood. Therefore, we established a systemwide portrait of KRAS- and extracellular signal–regulated kinase (ERK)–dependent gene transcription in KRAS-mutant cancer to delineate the molecular mechanisms of growth and of inhibitor resistance. Unexpectedly, our KRAS-dependent gene signature diverges substantially from the frequently cited Hallmark KRAS signaling gene signature, is driven predominantly through the ERK mitogen-activated protein kinase (MAPK) cascade, and accurately reflects KRAS- and ERK-regulated gene transcription in KRAS-mutant cancer patients. Integration with our ERK-regulated phospho- and total proteome highlights ERK deregulation of the anaphase promoting complex/cyclosome (APC/C) and other components of the cell cycle machinery as key processes that drive pancreatic ductal adenocarcinoma (PDAC) growth. Our findings elucidate mechanistically the critical role of ERK in driving KRAS-mutant tumor growth and in resistance to KRAS-ERK MAPK targeted therapies.
Defactinib, Pembrolizumab, and Gemcitabine in Patients with Advanced Treatment Refractory Pancreatic Cancer: A Phase I Dose Escalation and Expansion Study
Wang‐Gillam, Andrea , McWilliams, Robert R. , Suresh, Rama , Lockhart, A. Craig , Brown, Amberly , Breden, Marcus , Belle, Jad I. , Herndon, John M. , Bogner, Savannah J. , Tan, Benjamin , Boice, Nicholas , Acharya, Abhi , Abdiannia, Mina , Yoon, Harry H. , Zhu, Mojun , Aranha, Olivia , Herzog, Brett H. , Lim, Kian-Huat , McWilliams, Robert R , Suresh, Rama , Lockhart, Albert C , Brown, Amberly , Breden, Marcus , Belle, Jad I , Herndon, John , Bogner, Savannah J , Pedersen, Katrina , Tan, Benjamin , Boice, Nicholas , Acharya, Abhi , Abdiannia, Mina , Gao, Feng , Yoon, Harry H , Zhu, Mojun , Trikalinos, Nikolaos A , Ratner, Lee , Aranha, Olivia , Hawkins, William G , Herzog, Brett H , DeNardo, David G , Wang-Gillam, Andrea , Pedersen, Katrina S. , Gao, Feng , Trikalinos, Nikolaos A. , Ratner, Lee
Clinical Cancer Research | October 13, 2022 | Volume: 28 | Issue: 24 | Pages: 5254-5262
Abstract Purpose: Targeting focal adhesion kinase (FAK) renders checkpoint immunotherapy effective in pancreatic ductal adenocarcinoma (PDAC) mouse model. Defactinib is a highly potent oral FAK inhibitor that has a tolerable safety profile. Patients and Methods: We conducted a multicenter, open-label, phase I study with dose escalation and expansion phases. In dose escalation, patients with refractory solid tumors were treated at five escalating dose levels of defactinib and gemcitabine to identify a recommended phase II dose (RP2D). In expansion phase, patients with metastatic PDAC who progressed on frontline treatment (refractory cohort) or had stable disease (SD) after at least 4 months of standard gemcitabine/nab-paclitaxel (maintenance cohort) were treated at RP2D. Pre- and posttreatment tumor biopsies were performed to evaluate tumor immunity. Results: The triple drug combination was well-tolerated, with no dose-limiting toxicities. Among 20 treated patients with refractory PDAC, the disease control rate (DCR) was 80%, with one partial response (PR) and 15 SDs, and the median progression-free survival (PFS) and overall survival (OS) were 3.6 and 7.8 months, respectively. Among 10 evaluable patients in the maintenance cohort, DCR was 70% with one PR and six SDs. Three patients with SD came off study due to treatment- or disease-related complications. The median PFS and OS on study treatment were 5.0 and 8.3 months, respectively. Conclusions: The combination of defactinib, pembrolizumab, and gemcitabine was well-tolerated and safe, had promising preliminary efficacy, and showed biomarker activity in infiltrative T lymphocytes. Efficacy of this strategy may require incorporation of more potent chemotherapy in future studies.