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3. CHK1 protects oncogenic KRAS-expressing cells from DNA damage and is a target for pancreatic cancer treatment

Author

Klomp, Jennifer E., Lee, Ye S., Goodwin, Craig M., Papke, Björn, Klomp, Jeff A., Waters, Andrew M., Stalnecker, Clint A., DeLiberty, Jonathan M., Drizyte-Miller, Kristina, Yang, Runying, Diehl, J. Nathaniel, Yin, Hongwei H., Pierobon, Mariaelena, Baldelli, Elisa, Ryan, Meagan B., Li, Siqi, Peterson, Jackson, Smith, Amber R., Neal, James T., McCormick, Aaron K., Kuo, Calvin J., Counter, Christopher M., Petricoin, Emanuel F., III, Cox, Adrienne D., Bryant, Kirsten L., and Der, Channing J.

Published
2021
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4. First Responders and Mental Health

Author

Ryan, Meagan, primary, Hasan, Farah, additional, Molina, Lucero, additional, Cervoni, Cynthia, additional, Palladino, Jenna, additional, Vujanovic, Anka A., additional, and Gonzalez, Adam, additional

Published
2022
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5. WNT Activates the AAK1 Kinase to Promote Clathrin-Mediated Endocytosis of LRP6 and Establish a Negative Feedback Loop

Author

Agajanian, Megan J., Walker, Matthew P., Axtman, Alison D., Ruela-de-Sousa, Roberta R., Serafin, D. Stephen, Rabinowitz, Alex D., Graham, David M., Ryan, Meagan B., Tamir, Tigist, Nakamichi, Yuko, Gammons, Melissa V., Bennett, James M., Couñago, Rafael M., Drewry, David H., Elkins, Jonathan M., Gileadi, Carina, Gileadi, Opher, Godoi, Paulo H., Kapadia, Nirav, Müller, Susanne, Santiago, André S., Sorrell, Fiona J., Wells, Carrow I., Fedorov, Oleg, Willson, Timothy M., Zuercher, William J., and Major, Michael B.

Published
2019
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7. A Landscape of Therapeutic Cooperativity in KRAS Mutant Cancers Reveals Principles for Controlling Tumor Evolution

Author

Anderson, Grace R., Winter, Peter S., Lin, Kevin H., Nussbaum, Daniel P., Cakir, Merve, Stein, Elizabeth M., Soderquist, Ryan S., Crawford, Lorin, Leeds, Jim C., Newcomb, Rachel, Stepp, Priya, Yip, Catherine, Wardell, Suzanne E., Tingley, Jennifer P., Ali, Moiez, Xu, Mengmeng, Ryan, Meagan, McCall, Shannon J., McRee, Autumn J., Counter, Christopher M., Der, Channing J., and Wood, Kris C.

Published
2017
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14. Data from Clinical Acquired Resistance to KRASG12C Inhibition through a Novel KRAS Switch-II Pocket Mutation and Polyclonal Alterations Converging on RAS–MAPK Reactivation

Author

Tanaka, Noritaka, primary, Lin, Jessica J., primary, Li, Chendi, primary, Ryan, Meagan B., primary, Zhang, Junbing, primary, Kiedrowski, Lesli A., primary, Michel, Alexa G., primary, Syed, Mohammed U., primary, Fella, Katerina A., primary, Sakhi, Mustafa, primary, Baiev, Islam, primary, Juric, Dejan, primary, Gainor, Justin F., primary, Klempner, Samuel J., primary, Lennerz, Jochen K., primary, Siravegna, Giulia, primary, Bar-Peled, Liron, primary, Hata, Aaron N., primary, Heist, Rebecca S., primary, and Corcoran, Ryan B., primary

Published
2023
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17. Supplementary Data from Clinical Acquired Resistance to KRASG12C Inhibition through a Novel KRAS Switch-II Pocket Mutation and Polyclonal Alterations Converging on RAS–MAPK Reactivation

Author

Tanaka, Noritaka, primary, Lin, Jessica J., primary, Li, Chendi, primary, Ryan, Meagan B., primary, Zhang, Junbing, primary, Kiedrowski, Lesli A., primary, Michel, Alexa G., primary, Syed, Mohammed U., primary, Fella, Katerina A., primary, Sakhi, Mustafa, primary, Baiev, Islam, primary, Juric, Dejan, primary, Gainor, Justin F., primary, Klempner, Samuel J., primary, Lennerz, Jochen K., primary, Siravegna, Giulia, primary, Bar-Peled, Liron, primary, Hata, Aaron N., primary, Heist, Rebecca S., primary, and Corcoran, Ryan B., primary

Published
2023
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26. USP6 oncogene promotes Wnt signaling by deubiquitylating Frizzleds

Author

Madan, Babita, Walker, Matthew P., Young, Robert, Quick, Laura, Orgel, Kelly A., Ryan, Meagan, Gupta, Priti, Henrich, Ian C., Ferrer, Marc, Marine, Shane, Roberts, Brian S., Arthur, William T., Berndt, Jason D., Oliveira, Andre M., Moon, Randall T., Virshup, David M., Chou, Margaret M., and Major, Michael B.

Published
2016

38. Cell-Type-Specific Epigenetic Priming of Gene Expression in Nucleus Accumbens by Cocaine

Author

Mews, Philipp, primary, Van der Zee, Yentl, additional, Kronman, Hope, additional, Gurung, Ashik, additional, Ramakrishnan, Aarthi, additional, Browne, Caleb, additional, Futamura, Rita, additional, Estill, Molly, additional, Ryan, Meagan, additional, Reyes, Abner A, additional, Garcia, Benjamin A, additional, Sidoli, Simone, additional, Shen, Li, additional, and Nestler, Eric J, additional

Published
2022
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40. Clinical Acquired Resistance to KRASG12C Inhibition through a Novel KRAS Switch-II Pocket Mutation and Polyclonal Alterations Converging on RAS–MAPK Reactivation

Author

Tanaka, Noritaka, primary, Lin, Jessica J., additional, Li, Chendi, additional, Ryan, Meagan B., additional, Zhang, Junbing, additional, Kiedrowski, Lesli A., additional, Michel, Alexa G., additional, Syed, Mohammed U., additional, Fella, Katerina A., additional, Sakhi, Mustafa, additional, Baiev, Islam, additional, Juric, Dejan, additional, Gainor, Justin F., additional, Klempner, Samuel J., additional, Lennerz, Jochen K., additional, Siravegna, Giulia, additional, Bar-Peled, Liron, additional, Hata, Aaron N., additional, Heist, Rebecca S., additional, and Corcoran, Ryan B., additional

Published
2021
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46. AAK1 inhibits WNT signaling by promoting clathrin-mediated endocytosis of LRP6

Author

Agajanian, Megan J., primary, Walker, Matthew P., additional, Axtman, Alison D., additional, Ruela-de-Sousa, Roberta R., additional, Rabinowitz, Alex D., additional, Graham, David M., additional, Ryan, Meagan, additional, Serafin, D. Stephen, additional, Bennett, James M., additional, Couñago, Rafael M., additional, Drewry, David H., additional, Elkins, Jonathan M., additional, Gileadi, Carina, additional, Gileadi, Opher, additional, Godoi, Paulo H., additional, Kapadia, Nirav, additional, Müller, Susanne, additional, Santiago, André S., additional, Sorrell, Fiona J., additional, Wells, Carrow I., additional, Fedorov, Oleg, additional, Willson, Timothy M., additional, Zuercher, William J., additional, and Major, Michael B., additional

Published
2018
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47. A Transcription-uncoupled Negative Feedback Loop for the 1 WNT Pathway: WNT Activates the AAK1 Kinase to Promote Clathrin-mediated Endocytosis of LRP6

Author

Agajanian, Megan J., primary, Walker, Matthew P., additional, Axtman, Alison D., additional, Ruela-de-Sousa, Roberta R., additional, Rabinowitz, Alex D., additional, Graham, David M., additional, Ryan, Meagan, additional, Serafin, D. Stephen, additional, Gammons, Melissa V., additional, Bennett, James M., additional, Couuago, Rafael M., additional, Drewry, David H., additional, Elkins, Jonathan M., additional, Gileadi, Carina, additional, Gileadi, Opher, additional, Godoi, Paulo H., additional, Kapadia, Nirav, additional, MMller, Susanne, additional, Santiago, Andrr S., additional, Sorrell, Fiona J., additional, Wells, Carrow I., additional, Fedorov, Oleg, additional, Willson, Timothy M., additional, Zuercher, William J., additional, and Major, Michael B., additional

Published
2018
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48. TARGETING THE ERK MAPK PATHWAY IN RAS-DRIVEN CANCERS

Author

Ryan, Meagan

Abstract

RAS mutations are frequently found in the deadliest cancers in the United States, and there is a renewed interest in identifying therapeutic strategies to target RAS-driven cancers. While recent strategies to directly target mutant RAS have identified provocative small molecules, whether these can be developed into clinically potent and selective drugs remains to be seen. Arguably, among the most promising directions have been efforts to target protein kinase components of the effector pathways downstream of RAS. One of the best characterized effector pathways is the ERK mitogen-activated protein kinase (MAPK) cascade, a pathway that is critical in both the initiation and maintenance of NRAS- and BRAF-mutant melanoma as well as KRAS-mutant pancreatic ductal adenocarcinoma (PDAC). My research has focused on two aspects of the ERK MAPK cascade in these cancers: ERK regulation of the RAC small GTPase guanine nucleotide exchange factor (RACGEF) PREX1 in melanoma, and synergy between p38 MAPK and ERK inhibitors in PDAC. My studies in melanoma are focused on the RacGEF PREX1, a protein that has been previously identified as a driver of metastasis in an NRAS-driven genetically engineered mouse model of cancer. PREX1 is an activator of RAC1, also mutationally activated in melanoma. Previous work from our lab identified PREX1 as one of 82 genes regulated downstream of the ERK MAPK pathway in BRAF-mutant melanomas. Our lab also found that mice deficient in Prex1 were impaired in Nras-driven melanoma metastasis. My work has extended these studies on PREX1 to a broader panel of both NRAS- and BRAF-mutant melanomas. I found that expression of PREX1 protein is elevated in malignant melanomas compared to benign nevi and that high PREX1 protein expression is correlated with high levels of phosphorylated ERK. Loss of PREX1 reduced invasion in a context dependent manner and reduced levels of active RAC1-GTP, but not of the related GTPase CDC42. Also, the expression of PREX1 was regulated by ERK both transcriptionally and post-translationally. I found that the mechanisms of ERK driven overexpression of PREX1 in melanomas differs from those of PREX1 regulation previously identified in prostate cancer and breast cancer. Finally, my studies provide a mechanistic basis for a connection between the ERK MAPK cascade and RAC1, two pathways critical for the maintenance of melanomas. Since ERK MAPK pathway inhibitors are currently the standard of care in BRAF mutant melanomas, this connection warrants further study, especially in the context of therapeutic resistance. Therapeutic resistance to ERK MAPK cascade inhibition arises not only in BRAF-mutant melanomas, but also in other cancers driven by activation of the ERK MAPK cascade. KRAS-mutant pancreatic cancer is the third deadliest cancer in the United States and is dependent on the ERK MAPK cascade for both tumor development and maintenance. A recent study from our group found that a subset of KRAS-mutant PDAC cell lines and tumors are sensitive to the ERK inhibitors SCH772984 and BVD-523. I sought to validate a resistance mechanism to ERK inhibition first identified by this study, MAPK14 (p38α). Similar to ERK, p38 is the terminal kinase of a three-tiered MAPK cascade. We employed a novel CRISPR/Cas9 screen to identify mechanisms of resistance to the ERK inhibitor SCH772984 in KRAS-mutant pancreatic, lung, and colorectal cancers. MAPK14 was identified as a sensitizer to ERK inhibition and I validated that pharmacologic inhibition of p38 with the clinical candidate p38α/β inhibitor LY2228820 also sensitized PDAC to ERK inhibition. Concurrent p38 inhibition sensitized PDAC cell lines to the ERK inhibitors SCH772984 and BVD-523 in both anchorage-dependent and anchorage-independent growth. Concurrent p38 and ERK inhibition also led to an increase in G0/G1 cell cycle arrest vs ERK inhibitor treatment alone, while no enhancement in apoptosis was seen with dual inhibition vs ERK inhibitor alone. Mechanistically, ERK inhibitor treatment induced activation of the p38 MAPK cascade, including induction of expression of the p38 downstream substrate HSP27. Finally, concurrent p38 and ERK inhibition also enhanced loss of MYC, an oncogene critical for maintaining PDAC growth and previously identified by our group as a marker of sensitivity or resistance to ERK inhibition. My studies provide a mechanistic basis for synergy between p38 and ERK inhibition in PDAC that can be extended to additional KRAS-mutant cancers. In summary, my studies provide a rationale for the importance of the ERK MAPK cascade in RAS-driven cancers. ERK plays many roles in initiating and maintaining tumors of diverse genetic backgrounds, encompassing NRAS, KRAS, and BRAF mutations. Finally, my studies reveal the value in direct pharmacologic inhibition of ERK in RAS-driven cancers and in understanding resistance mechanisms to enhance ERK inhibitor therapeutic benefit.

Published
2016
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