Cooke, Sean F. and Wright, Thomas A. and Sin, Yuan Yan and Ling, Jiayue and Kyurkchieva, Elka and Phanthaphol, Nattaporn and McSkimming, Thomas and Herbert, Katharine and Rebus, Selma and Biankin, Andrew V. and Chang, David K. and Baillie, George S. and Blair, Connor M. (2024) Disruption of the pro-oncogenic c-RAF–PDE8A complex represents a differentiated approach to treating KRAS–c-RAF dependent PDAC. Scientific Reports, 14: 8998. ISSN 2045-2322
AI Summary:
A novel cell-penetrating peptide, DRx-170, has been developed to target c-RAF activity in KRASc-RAF dependent pancreatic ductal adenocarcinoma (PDAC).AI Topics:
Pancreatic ductal adenocarcinoma (PDAC) is considered the third leading cause of cancer mortality in the western world, offering advanced stage patients with few viable treatment options. Consequently, there remains an urgent unmet need to develop novel therapeutic strategies that can effectively inhibit pro-oncogenic molecular targets underpinning PDACs pathogenesis and progression. One such target is c-RAF, a downstream effector of RAS that is considered essential for the oncogenic growth and survival of mutant RAS-driven cancers (including KRASMT PDAC). Herein, we demonstrate how a novel cell-penetrating peptide disruptor (DRx-170) of the c-RAF–PDE8A protein–protein interaction (PPI) represents a differentiated approach to exploiting the c-RAF–cAMP/PKA signaling axes and treating KRAS–c-RAF dependent PDAC. Through disrupting the c-RAF–PDE8A protein complex, DRx-170 promotes the inactivation of c-RAF through an allosteric mechanism, dependent upon inactivating PKA phosphorylation. DRx-170 inhibits cell proliferation, adhesion and migration of a KRASMT PDAC cell line (PANC1), independent of ERK1/2 activity. Moreover, combining DRx-170 with afatinib significantly enhances PANC1 growth inhibition in both 2D and 3D cellular models. DRx-170 sensitivity appears to correlate with c-RAF dependency. This proof-of-concept study supports the development of DRx-170 as a novel and differentiated strategy for targeting c-RAF activity in KRAS–c-RAF dependent PDAC.
Cooke, Sean F.
Author
Cooke, Sean F. and Wright, Thomas A. and Sin, Yuan Yan and Ling, Jiayue and Kyurkchieva, Elka and Phanthaphol, Nattaporn and McSkimming, Thomas and Herbert, Katharine and Rebus, Selma and Biankin, Andrew V. and Chang, David K. and Baillie, George S. and Blair, Connor M. (2024) Disruption of the pro-oncogenic c-RAF–PDE8A complex represents a differentiated approach to treating KRAS–c-RAF dependent PDAC. Scientific Reports, 14: 8998. ISSN 2045-2322
See full publications listWright, Thomas A.
Author
Cooke, Sean F. and Wright, Thomas A. and Sin, Yuan Yan and Ling, Jiayue and Kyurkchieva, Elka and Phanthaphol, Nattaporn and McSkimming, Thomas and Herbert, Katharine and Rebus, Selma and Biankin, Andrew V. and Chang, David K. and Baillie, George S. and Blair, Connor M. (2024) Disruption of the pro-oncogenic c-RAF–PDE8A complex represents a differentiated approach to treating KRAS–c-RAF dependent PDAC. Scientific Reports, 14: 8998. ISSN 2045-2322
See full publications listSin, Yuan Yan
Author
Cooke, Sean F. and Wright, Thomas A. and Sin, Yuan Yan and Ling, Jiayue and Kyurkchieva, Elka and Phanthaphol, Nattaporn and McSkimming, Thomas and Herbert, Katharine and Rebus, Selma and Biankin, Andrew V. and Chang, David K. and Baillie, George S. and Blair, Connor M. (2024) Disruption of the pro-oncogenic c-RAF–PDE8A complex represents a differentiated approach to treating KRAS–c-RAF dependent PDAC. Scientific Reports, 14: 8998. ISSN 2045-2322
See full publications listLing, Jiayue
Author
Cooke, Sean F. and Wright, Thomas A. and Sin, Yuan Yan and Ling, Jiayue and Kyurkchieva, Elka and Phanthaphol, Nattaporn and McSkimming, Thomas and Herbert, Katharine and Rebus, Selma and Biankin, Andrew V. and Chang, David K. and Baillie, George S. and Blair, Connor M. (2024) Disruption of the pro-oncogenic c-RAF–PDE8A complex represents a differentiated approach to treating KRAS–c-RAF dependent PDAC. Scientific Reports, 14: 8998. ISSN 2045-2322
See full publications listKyurkchieva, Elka
Author
Cooke, Sean F. and Wright, Thomas A. and Sin, Yuan Yan and Ling, Jiayue and Kyurkchieva, Elka and Phanthaphol, Nattaporn and McSkimming, Thomas and Herbert, Katharine and Rebus, Selma and Biankin, Andrew V. and Chang, David K. and Baillie, George S. and Blair, Connor M. (2024) Disruption of the pro-oncogenic c-RAF–PDE8A complex represents a differentiated approach to treating KRAS–c-RAF dependent PDAC. Scientific Reports, 14: 8998. ISSN 2045-2322
See full publications listPhanthaphol, Nattaporn
Author
Cooke, Sean F. and Wright, Thomas A. and Sin, Yuan Yan and Ling, Jiayue and Kyurkchieva, Elka and Phanthaphol, Nattaporn and McSkimming, Thomas and Herbert, Katharine and Rebus, Selma and Biankin, Andrew V. and Chang, David K. and Baillie, George S. and Blair, Connor M. (2024) Disruption of the pro-oncogenic c-RAF–PDE8A complex represents a differentiated approach to treating KRAS–c-RAF dependent PDAC. Scientific Reports, 14: 8998. ISSN 2045-2322
See full publications listMcSkimming, Thomas
Author
Cooke, Sean F. and Wright, Thomas A. and Sin, Yuan Yan and Ling, Jiayue and Kyurkchieva, Elka and Phanthaphol, Nattaporn and McSkimming, Thomas and Herbert, Katharine and Rebus, Selma and Biankin, Andrew V. and Chang, David K. and Baillie, George S. and Blair, Connor M. (2024) Disruption of the pro-oncogenic c-RAF–PDE8A complex represents a differentiated approach to treating KRAS–c-RAF dependent PDAC. Scientific Reports, 14: 8998. ISSN 2045-2322
See full publications listHerbert, Katharine
Author
Cooke, Sean F. and Wright, Thomas A. and Sin, Yuan Yan and Ling, Jiayue and Kyurkchieva, Elka and Phanthaphol, Nattaporn and McSkimming, Thomas and Herbert, Katharine and Rebus, Selma and Biankin, Andrew V. and Chang, David K. and Baillie, George S. and Blair, Connor M. (2024) Disruption of the pro-oncogenic c-RAF–PDE8A complex represents a differentiated approach to treating KRAS–c-RAF dependent PDAC. Scientific Reports, 14: 8998. ISSN 2045-2322
See full publications listRebus, Selma
Author
Cooke, Sean F. and Wright, Thomas A. and Sin, Yuan Yan and Ling, Jiayue and Kyurkchieva, Elka and Phanthaphol, Nattaporn and McSkimming, Thomas and Herbert, Katharine and Rebus, Selma and Biankin, Andrew V. and Chang, David K. and Baillie, George S. and Blair, Connor M. (2024) Disruption of the pro-oncogenic c-RAF–PDE8A complex represents a differentiated approach to treating KRAS–c-RAF dependent PDAC. Scientific Reports, 14: 8998. ISSN 2045-2322
Pennel, Kathryn A.F. and Hatthakarnkul, Phimmada and Wood, Colin S. and Lian, Guang-Yu and Al-Badran, Sara and Quinn, Jean A. and Legrini, Assya and Inthagard, Jitwadee and Alexander, Peter G. and van Wyk, Hester and Kurniawan, Ahmad and Hashmi, Umar and Gillespie, Michael A. and Mills, Megan and Ammar, Aula and Hay, Jennifer and Andersen, Ditte and Nixon, Colin and Rebus, Selma and Chang, David K. and Kelly, Caroline and Harkin, Andrea and Graham, Janet and Church, David and Tomlinson, Ian and Saunders, Mark and Iveson, Tim and Lannagan, Tamsin R. M. and Jackstadt, Rene and Maka, Noori and Horgan, Paul G. and Roxburgh, Campbell S. D. and Sansom, Owen J. and McMillan, Donald C. and Steele, Colin W. and Jamieson, Nigel B. and Park, James H. and Roseweir, Antonia K. and Edwards, Joanne (2024) JAK/STAT3 represents a therapeutic target for colorectal cancer patients with stromal-rich tumors. Journal of Experimental and Clinical Cancer Research, 43: 64. ISSN 1756-9966
See full publications listBiankin, Andrew
Author
Casolino, Raffaella and Beer, Philip A. and Chakravarty, Debyani and Davis, Melissa B. and Malapelle, Umberto and Mazzarella, Luca and Normanno, Nicola and Pauli, Chantal and Subbiah, Vivek and Turnbull, Clare and Westphalen, C. Benedikt and Biankin, Andrew V. (2024) Interpreting and integrating genomic tests results in clinical cancer care: Overview and practical guidance. CA: A Cancer Journal for Clinicians, 74 (3). pp. 264-285. ISSN 0007-9235
Cooke, Sean F. and Wright, Thomas A. and Sin, Yuan Yan and Ling, Jiayue and Kyurkchieva, Elka and Phanthaphol, Nattaporn and McSkimming, Thomas and Herbert, Katharine and Rebus, Selma and Biankin, Andrew V. and Chang, David K. and Baillie, George S. and Blair, Connor M. (2024) Disruption of the pro-oncogenic c-RAF–PDE8A complex represents a differentiated approach to treating KRAS–c-RAF dependent PDAC. Scientific Reports, 14: 8998. ISSN 2045-2322
Agostini, Antonio and Piro, Geny and Inzani, Frediano and Quero, Giuseppe and Esposito, Annachiara and Caggiano, Alessia and Priori, Lorenzo and Larghi, Alberto and Alfieri, Sergio and Casolino, Raffaella and Scaglione, Giulia and Tondolo, Vincenzo and Cammarota, Giovanni and Ianiro, Gianluca and Corbo, Vincenzo and Biankin, Andrew V. and Tortora, Giampaolo and Carbone, Carmine (2024) Identification of spatially-resolved markers of malignant transformation in Intraductal Papillary Mucinous Neoplasms. Nature Communications, 15 (1): 2764. ISSN 2041-1723
See full publications listChang, David
Author
Cooke, Sean F. and Wright, Thomas A. and Sin, Yuan Yan and Ling, Jiayue and Kyurkchieva, Elka and Phanthaphol, Nattaporn and McSkimming, Thomas and Herbert, Katharine and Rebus, Selma and Biankin, Andrew V. and Chang, David K. and Baillie, George S. and Blair, Connor M. (2024) Disruption of the pro-oncogenic c-RAF–PDE8A complex represents a differentiated approach to treating KRAS–c-RAF dependent PDAC. Scientific Reports, 14: 8998. ISSN 2045-2322
Zhang, Shuman and Yun, Duo and Yang, Hao and Eckstein, Markus and Elbait, Gihan Daw and Zhou, Yaxing and Lu, Yanxi and Yang, Hai and Zhang, Jinping and Dörflein, Isabella and Britzen-Laurent, Nathalie and Pfeffer, Susanne and Stemmler, Marc P. and Dahl, Andreas and Mukhopadhyay, Debabrata and Chang, David and He, Hang and Zeng, Siyuan and Lan, Bin and Frey, Benjamin and Hampel, Chuanpit and Lentsch, Eva and Gollavilli, Paradesi Naidu and Büttner, Christian and Ekici, Arif B and Biankin, Andrew and Schneider-Stock, Regine and Ceppi, Paolo and Grützmann, Robert and Pilarsky, Christian (2024) Roflumilast inhibits tumor growth and migration in STK11/LKB1 deficient pancreatic cancer. Cell Death Discovery, 10: 124. ISSN 2058-7716
Pennel, Kathryn A.F. and Hatthakarnkul, Phimmada and Wood, Colin S. and Lian, Guang-Yu and Al-Badran, Sara and Quinn, Jean A. and Legrini, Assya and Inthagard, Jitwadee and Alexander, Peter G. and van Wyk, Hester and Kurniawan, Ahmad and Hashmi, Umar and Gillespie, Michael A. and Mills, Megan and Ammar, Aula and Hay, Jennifer and Andersen, Ditte and Nixon, Colin and Rebus, Selma and Chang, David K. and Kelly, Caroline and Harkin, Andrea and Graham, Janet and Church, David and Tomlinson, Ian and Saunders, Mark and Iveson, Tim and Lannagan, Tamsin R. M. and Jackstadt, Rene and Maka, Noori and Horgan, Paul G. and Roxburgh, Campbell S. D. and Sansom, Owen J. and McMillan, Donald C. and Steele, Colin W. and Jamieson, Nigel B. and Park, James H. and Roseweir, Antonia K. and Edwards, Joanne (2024) JAK/STAT3 represents a therapeutic target for colorectal cancer patients with stromal-rich tumors. Journal of Experimental and Clinical Cancer Research, 43: 64. ISSN 1756-9966
See full publications listBaillie, George S.
Author
Cooke, Sean F. and Wright, Thomas A. and Sin, Yuan Yan and Ling, Jiayue and Kyurkchieva, Elka and Phanthaphol, Nattaporn and McSkimming, Thomas and Herbert, Katharine and Rebus, Selma and Biankin, Andrew V. and Chang, David K. and Baillie, George S. and Blair, Connor M. (2024) Disruption of the pro-oncogenic c-RAF–PDE8A complex represents a differentiated approach to treating KRAS–c-RAF dependent PDAC. Scientific Reports, 14: 8998. ISSN 2045-2322
See full publications listBlair, Connor M.
Author
Cooke, Sean F. and Wright, Thomas A. and Sin, Yuan Yan and Ling, Jiayue and Kyurkchieva, Elka and Phanthaphol, Nattaporn and McSkimming, Thomas and Herbert, Katharine and Rebus, Selma and Biankin, Andrew V. and Chang, David K. and Baillie, George S. and Blair, Connor M. (2024) Disruption of the pro-oncogenic c-RAF–PDE8A complex represents a differentiated approach to treating KRAS–c-RAF dependent PDAC. Scientific Reports, 14: 8998. ISSN 2045-2322
See full publications listAvailable under License Creative Commons Attribution.
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