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3. ARAF mutations confer resistance to the RAF inhibitor belvarafenib in melanoma

Author

Yen, Ivana, Shanahan, Frances, Lee, Jeeyun, Hong, Yong Sang, Shin, Sang Joon, Moore, Amanda R., Sudhamsu, Jawahar, Chang, Matthew T., Bae, Inhwan, Dela Cruz, Darlene, Hunsaker, Thomas, Klijn, Christiaan, Liau, Nicholas P.D., Lin, Eva, Martin, Scott E., Mondrusan, Zora, and Piskol, Robert

Subjects
Antineoplastic agents -- Dosage and administration, Mutation (Biology) -- Health aspects, Protein kinases -- Physiological aspects, Melanoma -- Genetic aspects -- Drug therapy, Antimitotic agents -- Dosage and administration, Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

Although RAF monomer inhibitors (type I.5, BRAF(V600)) are clinically approved for the treatment of BRAF.sup.V600-mutant melanoma, they are ineffective in non-BRAF.sup.V600 mutant cells.sup.1-3. Belvarafenib is a potent and selective RAF dimer (type II) inhibitor that exhibits clinical activity in patients with BRAF.sup.V600E- and NRAS-mutant melanomas. Here we report the first-in-human phase I study investigating the maximum tolerated dose, and assessing the safety and preliminary efficacy of belvarafenib in BRAF.sup.V600E- and RAS-mutated advanced solid tumours (NCT02405065, NCT03118817). By generating belvarafenib-resistant NRAS-mutant melanoma cells and analysing circulating tumour DNA from patients treated with belvarafenib, we identified new recurrent mutations in ARAF within the kinase domain. ARAF mutants conferred resistance to belvarafenib in both a dimer- and a kinase activity-dependent manner. Belvarafenib induced ARAF mutant dimers, and dimers containing mutant ARAF were active in the presence of inhibitor. ARAF mutations may serve as a general resistance mechanism for RAF dimer inhibitors as the mutants exhibit reduced sensitivity to a panel of type II RAF inhibitors. The combination of RAF plus MEK inhibition may be used to delay ARAF-driven resistance and suggests a rational combination for clinical use. Together, our findings reveal specific and compensatory functions for the ARAF isoform and implicate ARAF mutations as a driver of resistance to RAF dimer inhibitors. The development, characterization and phase I clinical testing of the RAF inhibitor belvarafenib in cancer and a new resistance mechanism mediated by ARAF mutations are described., Author(s): Ivana Yen [sup.1] , Frances Shanahan [sup.1] , Jeeyun Lee [sup.2] [sup.3] , Yong Sang Hong [sup.4] , Sang Joon Shin [sup.5] , Amanda R. Moore [sup.1] , Jawahar [...]

Published
2021
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4. Computational Modeling of Drug Response Identifies Mutant-Specific Constraints for Dosing panRAF and MEK Inhibitors in Melanoma.

Author

Goetz, Andrew, Shanahan, Frances, Brooks, Logan, Lin, Eva, Mroue, Rana, Dela Cruz, Darlene, Hunsaker, Thomas, Czech, Bartosz, Dixit, Purushottam, Segal, Udi, Martin, Scott, Foster, Scott A., and Gerosa, Luca

Subjects
*PROTEIN kinase inhibitors, *COMPUTER simulation, *IN vitro studies, *MELANOMA, *RESEARCH funding, *ANTINEOPLASTIC agents, *XENOGRAFTS, *CELLULAR signal transduction, *DESCRIPTIVE statistics, *DOSE-effect relationship in pharmacology, *MICE, *CELL lines, *BIOINFORMATICS, *ANIMAL experimentation, *WESTERN immunoblotting, *PROTEIN-tyrosine kinases, *GENETIC mutation, *INDIVIDUALIZED medicine
Abstract

Simple Summary: Combining drugs is crucial for enhancing anti-cancer responses. However, the potential of pre-clinical data in identifying suitable combinations and dosage is often underutilized. In this study, we leverage pre-clinical in vitro cell line drug response data and computational modeling of signal transduction and of pharmacokinetics to elucidate distinct dose requirements for the combination of pan-RAF and MEK inhibitors in melanoma. Our findings reveal a more synergistic but narrower dosing landscape in NRAS vs. BRAF mutant melanoma, which we link to a mechanism of adaptive resistance through negative feedback. Further, our analysis suggests the importance of drug dosing strategies to optimize synergy based on mutational context yet highlights the real-world challenges of maintaining a narrow dose range. This approach establishes a framework for translational investigation of drug responses in the refinement of combination therapy, balancing the potential for synergy and practical feasibility in cancer treatment planning. Purpose: This study explores the potential of pre-clinical in vitro cell line response data and computational modeling in identifying the optimal dosage requirements of pan-RAF (Belvarafenib) and MEK (Cobimetinib) inhibitors in melanoma treatment. Our research is motivated by the critical role of drug combinations in enhancing anti-cancer responses and the need to close the knowledge gap around selecting effective dosing strategies to maximize their potential. Results: In a drug combination screen of 43 melanoma cell lines, we identified specific dosage landscapes of panRAF and MEK inhibitors for NRAS vs. BRAF mutant melanomas. Both experienced benefits, but with a notably more synergistic and narrow dosage range for NRAS mutant melanoma (mean Bliss score of 0.27 in NRAS vs. 0.1 in BRAF mutants). Computational modeling and follow-up molecular experiments attributed the difference to a mechanism of adaptive resistance by negative feedback. We validated the in vivo translatability of in vitro dose–response maps by predicting tumor growth in xenografts with high accuracy in capturing cytostatic and cytotoxic responses. We analyzed the pharmacokinetic and tumor growth data from Phase 1 clinical trials of Belvarafenib with Cobimetinib to show that the synergy requirement imposes stricter precision dose constraints in NRAS mutant melanoma patients. Conclusion: Leveraging pre-clinical data and computational modeling, our approach proposes dosage strategies that can optimize synergy in drug combinations, while also bringing forth the real-world challenges of staying within a precise dose range. Overall, this work presents a framework to aid dose selection in drug combinations. [ABSTRACT FROM AUTHOR]

Published
2024
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7. Supplementary Table 6 from Targeting the Replication Checkpoint Using SCH 900776, a Potent and Functionally Selective CHK1 Inhibitor Identified via High Content Screening

Author

Guzi, Timothy J., primary, Paruch, Kamil, primary, Dwyer, Michael P., primary, Labroli, Marc, primary, Shanahan, Frances, primary, Davis, Nicole, primary, Taricani, Lorena, primary, Wiswell, Derek, primary, Seghezzi, Wolfgang, primary, Penaflor, Ervin, primary, Bhagwat, Bhagyashree, primary, Wang, Wei, primary, Gu, Danling, primary, Hsieh, Yunsheng, primary, Lee, Suining, primary, Liu, Ming, primary, and Parry, David, primary

Published
2023
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8. Supplementary Figure 7 from Targeting the Replication Checkpoint Using SCH 900776, a Potent and Functionally Selective CHK1 Inhibitor Identified via High Content Screening

Author

Guzi, Timothy J., primary, Paruch, Kamil, primary, Dwyer, Michael P., primary, Labroli, Marc, primary, Shanahan, Frances, primary, Davis, Nicole, primary, Taricani, Lorena, primary, Wiswell, Derek, primary, Seghezzi, Wolfgang, primary, Penaflor, Ervin, primary, Bhagwat, Bhagyashree, primary, Wang, Wei, primary, Gu, Danling, primary, Hsieh, Yunsheng, primary, Lee, Suining, primary, Liu, Ming, primary, and Parry, David, primary

Published
2023
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9. Supplementary Table 3 from Targeting the Replication Checkpoint Using SCH 900776, a Potent and Functionally Selective CHK1 Inhibitor Identified via High Content Screening

Author

Guzi, Timothy J., primary, Paruch, Kamil, primary, Dwyer, Michael P., primary, Labroli, Marc, primary, Shanahan, Frances, primary, Davis, Nicole, primary, Taricani, Lorena, primary, Wiswell, Derek, primary, Seghezzi, Wolfgang, primary, Penaflor, Ervin, primary, Bhagwat, Bhagyashree, primary, Wang, Wei, primary, Gu, Danling, primary, Hsieh, Yunsheng, primary, Lee, Suining, primary, Liu, Ming, primary, and Parry, David, primary

Published
2023
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10. Supplementary Figure 1 from Targeting the Replication Checkpoint Using SCH 900776, a Potent and Functionally Selective CHK1 Inhibitor Identified via High Content Screening

Author

Guzi, Timothy J., primary, Paruch, Kamil, primary, Dwyer, Michael P., primary, Labroli, Marc, primary, Shanahan, Frances, primary, Davis, Nicole, primary, Taricani, Lorena, primary, Wiswell, Derek, primary, Seghezzi, Wolfgang, primary, Penaflor, Ervin, primary, Bhagwat, Bhagyashree, primary, Wang, Wei, primary, Gu, Danling, primary, Hsieh, Yunsheng, primary, Lee, Suining, primary, Liu, Ming, primary, and Parry, David, primary

Published
2023
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11. Supplementary Figure 9 from Targeting the Replication Checkpoint Using SCH 900776, a Potent and Functionally Selective CHK1 Inhibitor Identified via High Content Screening

Author

Guzi, Timothy J., primary, Paruch, Kamil, primary, Dwyer, Michael P., primary, Labroli, Marc, primary, Shanahan, Frances, primary, Davis, Nicole, primary, Taricani, Lorena, primary, Wiswell, Derek, primary, Seghezzi, Wolfgang, primary, Penaflor, Ervin, primary, Bhagwat, Bhagyashree, primary, Wang, Wei, primary, Gu, Danling, primary, Hsieh, Yunsheng, primary, Lee, Suining, primary, Liu, Ming, primary, and Parry, David, primary

Published
2023
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12. Supplementary Figure 2 from Targeting the Replication Checkpoint Using SCH 900776, a Potent and Functionally Selective CHK1 Inhibitor Identified via High Content Screening

Author

Guzi, Timothy J., primary, Paruch, Kamil, primary, Dwyer, Michael P., primary, Labroli, Marc, primary, Shanahan, Frances, primary, Davis, Nicole, primary, Taricani, Lorena, primary, Wiswell, Derek, primary, Seghezzi, Wolfgang, primary, Penaflor, Ervin, primary, Bhagwat, Bhagyashree, primary, Wang, Wei, primary, Gu, Danling, primary, Hsieh, Yunsheng, primary, Lee, Suining, primary, Liu, Ming, primary, and Parry, David, primary

Published
2023
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13. Supplementary Figure 4 from Targeting the Replication Checkpoint Using SCH 900776, a Potent and Functionally Selective CHK1 Inhibitor Identified via High Content Screening

Author

Guzi, Timothy J., primary, Paruch, Kamil, primary, Dwyer, Michael P., primary, Labroli, Marc, primary, Shanahan, Frances, primary, Davis, Nicole, primary, Taricani, Lorena, primary, Wiswell, Derek, primary, Seghezzi, Wolfgang, primary, Penaflor, Ervin, primary, Bhagwat, Bhagyashree, primary, Wang, Wei, primary, Gu, Danling, primary, Hsieh, Yunsheng, primary, Lee, Suining, primary, Liu, Ming, primary, and Parry, David, primary

Published
2023
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14. Supplementary Figure 3 from Targeting the Replication Checkpoint Using SCH 900776, a Potent and Functionally Selective CHK1 Inhibitor Identified via High Content Screening

Author

Guzi, Timothy J., primary, Paruch, Kamil, primary, Dwyer, Michael P., primary, Labroli, Marc, primary, Shanahan, Frances, primary, Davis, Nicole, primary, Taricani, Lorena, primary, Wiswell, Derek, primary, Seghezzi, Wolfgang, primary, Penaflor, Ervin, primary, Bhagwat, Bhagyashree, primary, Wang, Wei, primary, Gu, Danling, primary, Hsieh, Yunsheng, primary, Lee, Suining, primary, Liu, Ming, primary, and Parry, David, primary

Published
2023
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15. Supplementary Table 8 from Targeting the Replication Checkpoint Using SCH 900776, a Potent and Functionally Selective CHK1 Inhibitor Identified via High Content Screening

Author

Guzi, Timothy J., primary, Paruch, Kamil, primary, Dwyer, Michael P., primary, Labroli, Marc, primary, Shanahan, Frances, primary, Davis, Nicole, primary, Taricani, Lorena, primary, Wiswell, Derek, primary, Seghezzi, Wolfgang, primary, Penaflor, Ervin, primary, Bhagwat, Bhagyashree, primary, Wang, Wei, primary, Gu, Danling, primary, Hsieh, Yunsheng, primary, Lee, Suining, primary, Liu, Ming, primary, and Parry, David, primary

Published
2023
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16. Supplementary Figure 5 from Targeting the Replication Checkpoint Using SCH 900776, a Potent and Functionally Selective CHK1 Inhibitor Identified via High Content Screening

Author

Guzi, Timothy J., primary, Paruch, Kamil, primary, Dwyer, Michael P., primary, Labroli, Marc, primary, Shanahan, Frances, primary, Davis, Nicole, primary, Taricani, Lorena, primary, Wiswell, Derek, primary, Seghezzi, Wolfgang, primary, Penaflor, Ervin, primary, Bhagwat, Bhagyashree, primary, Wang, Wei, primary, Gu, Danling, primary, Hsieh, Yunsheng, primary, Lee, Suining, primary, Liu, Ming, primary, and Parry, David, primary

Published
2023
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17. Supplementary Table 7 from Targeting the Replication Checkpoint Using SCH 900776, a Potent and Functionally Selective CHK1 Inhibitor Identified via High Content Screening

Author

Guzi, Timothy J., primary, Paruch, Kamil, primary, Dwyer, Michael P., primary, Labroli, Marc, primary, Shanahan, Frances, primary, Davis, Nicole, primary, Taricani, Lorena, primary, Wiswell, Derek, primary, Seghezzi, Wolfgang, primary, Penaflor, Ervin, primary, Bhagwat, Bhagyashree, primary, Wang, Wei, primary, Gu, Danling, primary, Hsieh, Yunsheng, primary, Lee, Suining, primary, Liu, Ming, primary, and Parry, David, primary

Published
2023
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18. Supplementary Table 4 from Targeting the Replication Checkpoint Using SCH 900776, a Potent and Functionally Selective CHK1 Inhibitor Identified via High Content Screening

Author

Guzi, Timothy J., primary, Paruch, Kamil, primary, Dwyer, Michael P., primary, Labroli, Marc, primary, Shanahan, Frances, primary, Davis, Nicole, primary, Taricani, Lorena, primary, Wiswell, Derek, primary, Seghezzi, Wolfgang, primary, Penaflor, Ervin, primary, Bhagwat, Bhagyashree, primary, Wang, Wei, primary, Gu, Danling, primary, Hsieh, Yunsheng, primary, Lee, Suining, primary, Liu, Ming, primary, and Parry, David, primary

Published
2023
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19. Supplementary Figure 6 from Targeting the Replication Checkpoint Using SCH 900776, a Potent and Functionally Selective CHK1 Inhibitor Identified via High Content Screening

Author

Guzi, Timothy J., primary, Paruch, Kamil, primary, Dwyer, Michael P., primary, Labroli, Marc, primary, Shanahan, Frances, primary, Davis, Nicole, primary, Taricani, Lorena, primary, Wiswell, Derek, primary, Seghezzi, Wolfgang, primary, Penaflor, Ervin, primary, Bhagwat, Bhagyashree, primary, Wang, Wei, primary, Gu, Danling, primary, Hsieh, Yunsheng, primary, Lee, Suining, primary, Liu, Ming, primary, and Parry, David, primary

Published
2023
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20. Supplementary Table 2 from Targeting the Replication Checkpoint Using SCH 900776, a Potent and Functionally Selective CHK1 Inhibitor Identified via High Content Screening

Author

Guzi, Timothy J., primary, Paruch, Kamil, primary, Dwyer, Michael P., primary, Labroli, Marc, primary, Shanahan, Frances, primary, Davis, Nicole, primary, Taricani, Lorena, primary, Wiswell, Derek, primary, Seghezzi, Wolfgang, primary, Penaflor, Ervin, primary, Bhagwat, Bhagyashree, primary, Wang, Wei, primary, Gu, Danling, primary, Hsieh, Yunsheng, primary, Lee, Suining, primary, Liu, Ming, primary, and Parry, David, primary

Published
2023
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21. Supplementary Table 5 from Targeting the Replication Checkpoint Using SCH 900776, a Potent and Functionally Selective CHK1 Inhibitor Identified via High Content Screening

Author

Guzi, Timothy J., primary, Paruch, Kamil, primary, Dwyer, Michael P., primary, Labroli, Marc, primary, Shanahan, Frances, primary, Davis, Nicole, primary, Taricani, Lorena, primary, Wiswell, Derek, primary, Seghezzi, Wolfgang, primary, Penaflor, Ervin, primary, Bhagwat, Bhagyashree, primary, Wang, Wei, primary, Gu, Danling, primary, Hsieh, Yunsheng, primary, Lee, Suining, primary, Liu, Ming, primary, and Parry, David, primary

Published
2023
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22. Supplementary Figure 8 from Targeting the Replication Checkpoint Using SCH 900776, a Potent and Functionally Selective CHK1 Inhibitor Identified via High Content Screening

Author

Guzi, Timothy J., primary, Paruch, Kamil, primary, Dwyer, Michael P., primary, Labroli, Marc, primary, Shanahan, Frances, primary, Davis, Nicole, primary, Taricani, Lorena, primary, Wiswell, Derek, primary, Seghezzi, Wolfgang, primary, Penaflor, Ervin, primary, Bhagwat, Bhagyashree, primary, Wang, Wei, primary, Gu, Danling, primary, Hsieh, Yunsheng, primary, Lee, Suining, primary, Liu, Ming, primary, and Parry, David, primary

Published
2023
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23. Supplementary Figure Legends from Targeting the Replication Checkpoint Using SCH 900776, a Potent and Functionally Selective CHK1 Inhibitor Identified via High Content Screening

Author

Guzi, Timothy J., primary, Paruch, Kamil, primary, Dwyer, Michael P., primary, Labroli, Marc, primary, Shanahan, Frances, primary, Davis, Nicole, primary, Taricani, Lorena, primary, Wiswell, Derek, primary, Seghezzi, Wolfgang, primary, Penaflor, Ervin, primary, Bhagwat, Bhagyashree, primary, Wang, Wei, primary, Gu, Danling, primary, Hsieh, Yunsheng, primary, Lee, Suining, primary, Liu, Ming, primary, and Parry, David, primary

Published
2023
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24. Supplementary Table 1 from Targeting the Replication Checkpoint Using SCH 900776, a Potent and Functionally Selective CHK1 Inhibitor Identified via High Content Screening

Author

Guzi, Timothy J., primary, Paruch, Kamil, primary, Dwyer, Michael P., primary, Labroli, Marc, primary, Shanahan, Frances, primary, Davis, Nicole, primary, Taricani, Lorena, primary, Wiswell, Derek, primary, Seghezzi, Wolfgang, primary, Penaflor, Ervin, primary, Bhagwat, Bhagyashree, primary, Wang, Wei, primary, Gu, Danling, primary, Hsieh, Yunsheng, primary, Lee, Suining, primary, Liu, Ming, primary, and Parry, David, primary

Published
2023
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25. Data from Targeting the Replication Checkpoint Using SCH 900776, a Potent and Functionally Selective CHK1 Inhibitor Identified via High Content Screening

Author

Guzi, Timothy J., primary, Paruch, Kamil, primary, Dwyer, Michael P., primary, Labroli, Marc, primary, Shanahan, Frances, primary, Davis, Nicole, primary, Taricani, Lorena, primary, Wiswell, Derek, primary, Seghezzi, Wolfgang, primary, Penaflor, Ervin, primary, Bhagwat, Bhagyashree, primary, Wang, Wei, primary, Gu, Danling, primary, Hsieh, Yunsheng, primary, Lee, Suining, primary, Liu, Ming, primary, and Parry, David, primary

Published
2023
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26. Data Supplement from Targeting the Replication Checkpoint Using SCH 900776, a Potent and Functionally Selective CHK1 Inhibitor Identified via High Content Screening

Author

Guzi, Timothy J., primary, Paruch, Kamil, primary, Dwyer, Michael P., primary, Labroli, Marc, primary, Shanahan, Frances, primary, Davis, Nicole, primary, Taricani, Lorena, primary, Wiswell, Derek, primary, Seghezzi, Wolfgang, primary, Penaflor, Ervin, primary, Bhagwat, Bhagyashree, primary, Wang, Wei, primary, Gu, Danling, primary, Hsieh, Yunsheng, primary, Lee, Suining, primary, Liu, Ming, primary, and Parry, David, primary

Published
2023
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27. Supplementary Table 2 from Dinaciclib (SCH 727965), a Novel and Potent Cyclin-Dependent Kinase Inhibitor

Author

Parry, David, primary, Guzi, Timothy, primary, Shanahan, Frances, primary, Davis, Nicole, primary, Prabhavalkar, Deepa, primary, Wiswell, Derek, primary, Seghezzi, Wolfgang, primary, Paruch, Kamil, primary, Dwyer, Michael P., primary, Doll, Ronald, primary, Nomeir, Amin, primary, Windsor, William, primary, Fischmann, Thierry, primary, Wang, Yaolin, primary, Oft, Martin, primary, Chen, Taiying, primary, Kirschmeier, Paul, primary, and Lees, Emma M., primary

Published
2023
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28. Data from Dinaciclib (SCH 727965), a Novel and Potent Cyclin-Dependent Kinase Inhibitor

Author

Parry, David, primary, Guzi, Timothy, primary, Shanahan, Frances, primary, Davis, Nicole, primary, Prabhavalkar, Deepa, primary, Wiswell, Derek, primary, Seghezzi, Wolfgang, primary, Paruch, Kamil, primary, Dwyer, Michael P., primary, Doll, Ronald, primary, Nomeir, Amin, primary, Windsor, William, primary, Fischmann, Thierry, primary, Wang, Yaolin, primary, Oft, Martin, primary, Chen, Taiying, primary, Kirschmeier, Paul, primary, and Lees, Emma M., primary

Published
2023
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29. Supplementary Table 1 from Dinaciclib (SCH 727965), a Novel and Potent Cyclin-Dependent Kinase Inhibitor

Author

Parry, David, primary, Guzi, Timothy, primary, Shanahan, Frances, primary, Davis, Nicole, primary, Prabhavalkar, Deepa, primary, Wiswell, Derek, primary, Seghezzi, Wolfgang, primary, Paruch, Kamil, primary, Dwyer, Michael P., primary, Doll, Ronald, primary, Nomeir, Amin, primary, Windsor, William, primary, Fischmann, Thierry, primary, Wang, Yaolin, primary, Oft, Martin, primary, Chen, Taiying, primary, Kirschmeier, Paul, primary, and Lees, Emma M., primary

Published
2023
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31. CRAF dimerization with ARAF regulates KRAS-driven tumor growth

Author

Venkatanarayan, Avinashnarayan, primary, Liang, Jason, additional, Yen, Ivana, additional, Shanahan, Frances, additional, Haley, Benjamin, additional, Phu, Lilian, additional, Verschueren, Erik, additional, Hinkle, Trent B., additional, Kan, David, additional, Segal, Ehud, additional, Long, Jason E., additional, Lima, Tony, additional, Liau, Nicholas P.D., additional, Sudhamsu, Jawahar, additional, Li, Jason, additional, Klijn, Christiaan, additional, Piskol, Robert, additional, Junttila, Melissa R., additional, Shaw, Andrey S., additional, Merchant, Mark, additional, Chang, Matthew T., additional, Kirkpatrick, Donald S., additional, and Malek, Shiva, additional

Published
2022
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32. Identifying transcriptional programs underlying cancer drug response with TraCe-seq

Author

Chang, Matthew T., primary, Shanahan, Frances, additional, Nguyen, Thi Thu Thao, additional, Staben, Steven T., additional, Gazzard, Lewis, additional, Yamazoe, Sayumi, additional, Wertz, Ingrid E., additional, Piskol, Robert, additional, Yang, Yeqing Angela, additional, Modrusan, Zora, additional, Haley, Benjamin, additional, Evangelista, Marie, additional, Malek, Shiva, additional, Foster, Scott A., additional, and Ye, Xin, additional

Published
2021
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34. Targeting KRAS Mutant Cancers via Combination Treatment: Discovery of a Pyridopyridazinone pan-RAF Kinase Inhibitor

Author

Huestis, Malcolm P., primary, Durk, Matthew R., additional, Eigenbrot, Charles, additional, Gibbons, Paul, additional, Hunsaker, Thomas L., additional, La, Hank, additional, Leung, Dennis H., additional, Liu, Wendy, additional, Malek, Shiva, additional, Merchant, Mark, additional, Moffat, John G., additional, Muli, Christine S., additional, Orr, Christine J., additional, Parr, Brendan T., additional, Shanahan, Frances, additional, Sneeringer, Christopher J., additional, Wang, Weiru, additional, Yen, Ivana, additional, Yin, Jianping, additional, Rudolph, Joachim, additional, and Siu, Michael, additional

Published
2021
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35. Targeting KRAS Mutant Cancers via Combination Treatment: Discovery of a 5-Fluoro-4-(3H)-quinazolinone Aryl Urea pan-RAF Kinase Inhibitor

Author

Huestis, Malcolm P., primary, Dela Cruz, Darlene, additional, DiPasquale, Antonio G., additional, Durk, Matthew R., additional, Eigenbrot, Charles, additional, Gibbons, Paul, additional, Gobbi, Alberto, additional, Hunsaker, Thomas L., additional, La, Hank, additional, Leung, Dennis H., additional, Liu, Wendy, additional, Malek, Shiva, additional, Merchant, Mark, additional, Moffat, John G., additional, Muli, Christine S., additional, Orr, Christine J., additional, Parr, Brendan T., additional, Shanahan, Frances, additional, Sneeringer, Christopher J., additional, Wang, Weiru, additional, Yen, Ivana, additional, Yin, Jianping, additional, Siu, Michael, additional, and Rudolph, Joachim, additional

Published
2021
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38. ARAFmutations confer resistance to the RAF inhibitor belvarafenib in melanoma

Author

Yen, Ivana, Shanahan, Frances, Lee, Jeeyun, Hong, Yong Sang, Shin, Sang Joon, Moore, Amanda R., Sudhamsu, Jawahar, Chang, Matthew T., Bae, Inhwan, Dela Cruz, Darlene, Hunsaker, Thomas, Klijn, Christiaan, Liau, Nicholas P. D., Lin, Eva, Martin, Scott E., Modrusan, Zora, Piskol, Robert, Segal, Ehud, Venkatanarayan, Avinashnarayan, Ye, Xin, Yin, Jianping, Zhang, Liangxuan, Kim, Jin-Soo, Lim, Hyeong-Seok, Kim, Kyu-Pyo, Kim, Yu Jung, Han, Hye Sook, Lee, Soo Jung, Kim, Seung Tae, Jung, Minkyu, Hong, Yoon-hee, Noh, Young Su, Choi, Munjeong, Han, Oakpil, Nowicka, Malgorzata, Srinivasan, Shrividhya, Yan, Yibing, Kim, Tae Won, and Malek, Shiva

Abstract

Although RAF monomer inhibitors (type I.5, BRAF(V600)) are clinically approved for the treatment of BRAFV600-mutant melanoma, they are ineffective in non-BRAFV600mutant cells1–3. Belvarafenib is a potent and selective RAF dimer (type II) inhibitor that exhibits clinical activity in patients with BRAFV600E-and NRAS-mutant melanomas. Here we report the first-in-human phase I study investigating the maximum tolerated dose, and assessing the safety and preliminary efficacy of belvarafenib in BRAFV600E- and RAS-mutated advanced solid tumours (NCT02405065, NCT03118817). By generating belvarafenib-resistant NRAS-mutant melanoma cells and analysing circulating tumour DNA from patients treated with belvarafenib, we identified new recurrent mutations in ARAFwithin the kinase domain. ARAF mutants conferred resistance to belvarafenib in both a dimer- and a kinase activity-dependent manner. Belvarafenib induced ARAF mutant dimers, and dimers containing mutant ARAF were active in the presence of inhibitor. ARAFmutations may serve as a general resistance mechanism for RAF dimer inhibitors as the mutants exhibit reduced sensitivity to a panel of type II RAF inhibitors. The combination of RAF plus MEK inhibition may be used to delay ARAF-driven resistance and suggests a rational combination for clinical use. Together, our findings reveal specific and compensatory functions for the ARAF isoform and implicate ARAFmutations as a driver of resistance to RAF dimer inhibitors.

Published
2021
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39. Pharmacological Induction of RAS-GTP Confers RAF Inhibitor Sensitivity in KRAS Mutant Tumors

Author

Yen, Ivana, primary, Shanahan, Frances, additional, Merchant, Mark, additional, Orr, Christine, additional, Hunsaker, Thomas, additional, Durk, Matthew, additional, La, Hank, additional, Zhang, Xiaolin, additional, Martin, Scott E., additional, Lin, Eva, additional, Chan, John, additional, Yu, Yihong, additional, Amin, Dhara, additional, Neve, Richard M., additional, Gustafson, Amy, additional, Venkatanarayan, Avinashnarayan, additional, Foster, Scott A., additional, Rudolph, Joachim, additional, Klijn, Christiaan, additional, and Malek, Shiva, additional

Published
2018
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40. Abstract 874: Pharmacologically induced RAS-GTP levels and CRAF-BRAF hetero-dimerization drive sensitization to Type II pan-RAF inhibitors in KRAS mutant cancer

Author

Klijn, Christiaan N., primary, Yen, Ivana, additional, Shanahan, Frances, additional, Merchant, Mark, additional, Orr, Christine, additional, Hunsaker, Thomas, additional, Durk, Matthew, additional, La, Hank, additional, Zhang, Xiaoling, additional, Martin, Scott, additional, Lin, Eva, additional, Chan, John, additional, Yu, Yihong, additional, Amin, Dhara, additional, Gustafson, Amy, additional, Foster, Scott, additional, Rudolph, Joachim, additional, and Malek, Shiva, additional

Published
2018
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41. The Molecular Basis of Canine Fucosidosis

Author

Barker, Christopher, Fukushima, Hisao, Shanahan, Frances, O’Brien, John, de Wet, Jeffrey, Willems, Patrick, Winchester, Bryan, Salvayre, Robert, editor, Douste-Blazy, Louis, editor, and Gatt, Shimon, editor

Published
1988
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42. Abstract 4967: RAF kinase inhibition synergizes with MEK inhibitors in KRAS mutant tumors

Author

Yen, Ivana, primary, Klijn, Christiaan, additional, Shanahan, Frances, additional, Merchant, Mark, additional, Orr, Christine, additional, Hunsaker, Thomas, additional, Durk, Matthew, additional, La, Hank, additional, Zhang, Xiaolin, additional, Martin, Scott, additional, Lin, Eva, additional, Chan, John, additional, Yu, Yihong, additional, Gustafson, Amy, additional, Rudolph, Joachim, additional, and Malek, Shiva, additional

Published
2017
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43. Project DRIVE: A Compendium of Cancer Dependencies and Synthetic Lethal Relationships Uncovered by Large-Scale, Deep RNAi Screening

Author

McDonald, E. Robert, primary, de Weck, Antoine, additional, Schlabach, Michael R., additional, Billy, Eric, additional, Mavrakis, Konstantinos J., additional, Hoffman, Gregory R., additional, Belur, Dhiren, additional, Castelletti, Deborah, additional, Frias, Elizabeth, additional, Gampa, Kalyani, additional, Golji, Javad, additional, Kao, Iris, additional, Li, Li, additional, Megel, Philippe, additional, Perkins, Thomas A., additional, Ramadan, Nadire, additional, Ruddy, David A., additional, Silver, Serena J., additional, Sovath, Sosathya, additional, Stump, Mark, additional, Weber, Odile, additional, Widmer, Roland, additional, Yu, Jianjun, additional, Yu, Kristine, additional, Yue, Yingzi, additional, Abramowski, Dorothee, additional, Ackley, Elizabeth, additional, Barrett, Rosemary, additional, Berger, Joel, additional, Bernard, Julie L., additional, Billig, Rebecca, additional, Brachmann, Saskia M., additional, Buxton, Frank, additional, Caothien, Roger, additional, Caushi, Justina X., additional, Chung, Franklin S., additional, Cortés-Cros, Marta, additional, deBeaumont, Rosalie S., additional, Delaunay, Clara, additional, Desplat, Aurore, additional, Duong, William, additional, Dwoske, Donald A., additional, Eldridge, Richard S., additional, Farsidjani, Ali, additional, Feng, Fei, additional, Feng, JiaJia, additional, Flemming, Daisy, additional, Forrester, William, additional, Galli, Giorgio G., additional, Gao, Zhenhai, additional, Gauter, François, additional, Gibaja, Veronica, additional, Haas, Kristy, additional, Hattenberger, Marc, additional, Hood, Tami, additional, Hurov, Kristen E., additional, Jagani, Zainab, additional, Jenal, Mathias, additional, Johnson, Jennifer A., additional, Jones, Michael D., additional, Kapoor, Avnish, additional, Korn, Joshua, additional, Liu, Jilin, additional, Liu, Qiumei, additional, Liu, Shumei, additional, Liu, Yue, additional, Loo, Alice T., additional, Macchi, Kaitlin J., additional, Martin, Typhaine, additional, McAllister, Gregory, additional, Meyer, Amandine, additional, Mollé, Sandra, additional, Pagliarini, Raymond A., additional, Phadke, Tanushree, additional, Repko, Brian, additional, Schouwey, Tanja, additional, Shanahan, Frances, additional, Shen, Qiong, additional, Stamm, Christelle, additional, Stephan, Christine, additional, Stucke, Volker M., additional, Tiedt, Ralph, additional, Varadarajan, Malini, additional, Venkatesan, Kavitha, additional, Vitari, Alberto C., additional, Wallroth, Marco, additional, Weiler, Jan, additional, Zhang, Jing, additional, Mickanin, Craig, additional, Myer, Vic E., additional, Porter, Jeffery A., additional, Lai, Albert, additional, Bitter, Hans, additional, Lees, Emma, additional, Keen, Nicholas, additional, Kauffmann, Audrey, additional, Stegmeier, Frank, additional, Hofmann, Francesco, additional, Schmelzle, Tobias, additional, and Sellers, William R., additional

Published
2017
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44. Phase I Dose-Escalation Trial of Checkpoint Kinase 1 Inhibitor MK-8776 As Monotherapy and in Combination With Gemcitabine in Patients With Advanced Solid Tumors

Author

Daud, Adil I., primary, Ashworth, Michelle T., additional, Strosberg, Jonathan, additional, Goldman, Jonathan W., additional, Mendelson, David, additional, Springett, Gregory, additional, Venook, Alan P., additional, Loechner, Sabine, additional, Rosen, Lee S., additional, Shanahan, Frances, additional, Parry, David, additional, Shumway, Stuart, additional, Grabowsky, Jennifer A., additional, Freshwater, Tomoko, additional, Sorge, Christopher, additional, Kang, Soonmo Peter, additional, Isaacs, Randi, additional, and Munster, Pamela N., additional

Published
2015
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46. Targeting the Replication Checkpoint Using SCH 900776, a Potent and Functionally Selective CHK1 Inhibitor Identified via High Content Screening

Author

Guzi, Timothy J., primary, Paruch, Kamil, additional, Dwyer, Michael P., additional, Labroli, Marc, additional, Shanahan, Frances, additional, Davis, Nicole, additional, Taricani, Lorena, additional, Wiswell, Derek, additional, Seghezzi, Wolfgang, additional, Penaflor, Ervin, additional, Bhagwat, Bhagyashree, additional, Wang, Wei, additional, Gu, Danling, additional, Hsieh, Yunsheng, additional, Lee, Suining, additional, Liu, Ming, additional, and Parry, David, additional

Published
2011
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48. Dinaciclib (SCH 727965), a Novel and Potent Cyclin-Dependent Kinase Inhibitor

Author

Parry, David, primary, Guzi, Timothy, additional, Shanahan, Frances, additional, Davis, Nicole, additional, Prabhavalkar, Deepa, additional, Wiswell, Derek, additional, Seghezzi, Wolfgang, additional, Paruch, Kamil, additional, Dwyer, Michael P., additional, Doll, Ronald, additional, Nomeir, Amin, additional, Windsor, William, additional, Fischmann, Thierry, additional, Wang, Yaolin, additional, Oft, Martin, additional, Chen, Taiying, additional, Kirschmeier, Paul, additional, and Lees, Emma M., additional

Published
2010
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49. Discovery of Dinaciclib (SCH 727965): A Potent and Selective Inhibitor of Cyclin-Dependent Kinases

Author

Paruch, Kamil, primary, Dwyer, Michael P., additional, Alvarez, Carmen, additional, Brown, Courtney, additional, Chan, Tin-Yau, additional, Doll, Ronald J., additional, Keertikar, Kerry, additional, Knutson, Chad, additional, McKittrick, Brian, additional, Rivera, Jocelyn, additional, Rossman, Randall, additional, Tucker, Greg, additional, Fischmann, Thierry, additional, Hruza, Alan, additional, Madison, Vincent, additional, Nomeir, Amin A., additional, Wang, Yaolin, additional, Kirschmeier, Paul, additional, Lees, Emma, additional, Parry, David, additional, Sgambellone, Nicole, additional, Seghezzi, Wolfgang, additional, Schultz, Lesley, additional, Shanahan, Frances, additional, Wiswell, Derek, additional, Xu, Xiaoying, additional, Zhou, Quiao, additional, James, Ray A., additional, Paradkar, Vidyadhar M., additional, Park, Haengsoon, additional, Rokosz, Laura R., additional, Stauffer, Tara M., additional, and Guzi, Timothy J., additional

Published
2010
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