Scaffolding Protein Connector Enhancer of Kinase Suppressor of Ras 1 (CNKSR1) Regulates MAPK Inhibition Responsiveness in Pancreas Cancer Via Crosstalk with AKT Signaling

Overview

Journal Mol Cancer Res

Specialty Cell Biology

Date 2023 Feb 15

PMID 36790955

Authors

Dandan Li

Anne M Miermont

Rushikesh Sable

Humair S Quadri

Lesley A Mathews Griner

Scott E Martin

Taivan Odzorig

Soumita De

Marc Ferrer

Astin S Powers

Stephen M Hewitt

Udo Rudloff

Affiliations

Soon will be listed here.

Abstract

Implications: The CNKSR1 scaffold, identified within an RNAi screen as a novel mediator of resistance to MEK inhibition in pancreas cancer, connects the MAPK pathway and AKT signaling and may be adopted as a biomarker to select patients for combined MEK AKT blockade.

Citing Articles

Identification of CNKSR1 as a biomarker for "cold" tumor microenvironment in lung adenocarcinoma: An integrative analysis based on a novel workflow.

Cai Q, Peng M Heliyon. 2024; 10(8):e29126.

PMID: 38628722 PMC: 11019179. DOI: 10.1016/j.heliyon.2024.e29126.

References

Fritz R, Radziwill G . CNK1 promotes invasion of cancer cells through NF-kappaB-dependent signaling. Mol Cancer Res. 2010; 8(3):395-406. DOI: 10.1158/1541-7786.MCR-09-0296. View

Brennan D, Dar A, Hertz N, Chao W, Burlingame A, Shokat K . A Raf-induced allosteric transition of KSR stimulates phosphorylation of MEK. Nature. 2011; 472(7343):366-9. DOI: 10.1038/nature09860. View

Quadri H, Aiken T, Allgaeuer M, Moravec R, Altekruse S, Hussain S . Expression of the scaffold connector enhancer of kinase suppressor of Ras 1 (CNKSR1) is correlated with clinical outcome in pancreatic cancer. BMC Cancer. 2017; 17(1):495. PMC: 5522593. DOI: 10.1186/s12885-017-3481-4. View

Claperon A, Therrien M . KSR and CNK: two scaffolds regulating RAS-mediated RAF activation. Oncogene. 2007; 26(22):3143-58. DOI: 10.1038/sj.onc.1210408. View

Fischer A, Warscheid B, Weber W, Radziwill G . Optogenetic clustering of CNK1 reveals mechanistic insights in RAF and AKT signalling controlling cell fate decisions. Sci Rep. 2016; 6:38155. PMC: 5128868. DOI: 10.1038/srep38155. View

Drilon A, Laetsch T, Kummar S, Dubois S, Lassen U, Demetri G . Efficacy of Larotrectinib in TRK Fusion-Positive Cancers in Adults and Children. N Engl J Med. 2018; 378(8):731-739. PMC: 5857389. DOI: 10.1056/NEJMoa1714448. View

Chung V, McDonough S, Philip P, Cardin D, Wang-Gillam A, Hui L . Effect of Selumetinib and MK-2206 vs Oxaliplatin and Fluorouracil in Patients With Metastatic Pancreatic Cancer After Prior Therapy: SWOG S1115 Study Randomized Clinical Trial. JAMA Oncol. 2016; 3(4):516-522. PMC: 5665683. DOI: 10.1001/jamaoncol.2016.5383. View

Dutruel C, Bergmann F, Rooman I, Zucknick M, Weichenhan D, Geiselhart L . Early epigenetic downregulation of WNK2 kinase during pancreatic ductal adenocarcinoma development. Oncogene. 2013; 33(26):3401-10. DOI: 10.1038/onc.2013.312. View

Wong W, Raufi A, Safyan R, Bates S, Manji G . BRCA Mutations in Pancreas Cancer: Spectrum, Current Management, Challenges and Future Prospects. Cancer Manag Res. 2020; 12:2731-2742. PMC: 7185320. DOI: 10.2147/CMAR.S211151. View

10.

Rabizadeh S, Xavier R, Ishiguro K, Bernabeortiz J, Lopez-Ilasaca M, Khokhlatchev A . The scaffold protein CNK1 interacts with the tumor suppressor RASSF1A and augments RASSF1A-induced cell death. J Biol Chem. 2004; 279(28):29247-54. DOI: 10.1074/jbc.M401699200. View

11.

Kun E, Tsang Y, Ng C, Gershenson D, Wong K . MEK inhibitor resistance mechanisms and recent developments in combination trials. Cancer Treat Rev. 2020; 92:102137. DOI: 10.1016/j.ctrv.2020.102137. View

12.

Singh A, Greninger P, Rhodes D, Koopman L, Violette S, Bardeesy N . A gene expression signature associated with "K-Ras addiction" reveals regulators of EMT and tumor cell survival. Cancer Cell. 2009; 15(6):489-500. PMC: 2743093. DOI: 10.1016/j.ccr.2009.03.022. View

13.

Lito P, Saborowski A, Yue J, Solomon M, Joseph E, Gadal S . Disruption of CRAF-mediated MEK activation is required for effective MEK inhibition in KRAS mutant tumors. Cancer Cell. 2014; 25(5):697-710. PMC: 4049532. DOI: 10.1016/j.ccr.2014.03.011. View

14.

Fischer A, Weber W, Warscheid B, Radziwill G . AKT-dependent phosphorylation of the SAM domain induces oligomerization and activation of the scaffold protein CNK1. Biochim Biophys Acta Mol Cell Res. 2016; 1864(1):89-100. DOI: 10.1016/j.bbamcr.2016.10.009. View

15.

Gysin S, Lee S, Dean N, McMahon M . Pharmacologic inhibition of RAF-->MEK-->ERK signaling elicits pancreatic cancer cell cycle arrest through induced expression of p27Kip1. Cancer Res. 2005; 65(11):4870-80. DOI: 10.1158/0008-5472.CAN-04-2848. View

16.

McKay M, Ritt D, Morrison D . Signaling dynamics of the KSR1 scaffold complex. Proc Natl Acad Sci U S A. 2009; 106(27):11022-7. PMC: 2708738. DOI: 10.1073/pnas.0901590106. View

17.

Douziech M, Sahmi M, Laberge G, Therrien M . A KSR/CNK complex mediated by HYP, a novel SAM domain-containing protein, regulates RAS-dependent RAF activation in Drosophila. Genes Dev. 2006; 20(7):807-19. PMC: 1472284. DOI: 10.1101/gad.1390406. View

18.

Fritz R, Varga Z, Radziwill G . CNK1 is a novel Akt interaction partner that promotes cell proliferation through the Akt-FoxO signalling axis. Oncogene. 2010; 29(24):3575-82. DOI: 10.1038/onc.2010.104. View

19.

Yuan X, Tang Z, Du R, Yao Z, Cheung S, Zhang X . RAF dimer inhibition enhances the antitumor activity of MEK inhibitors in K-RAS mutant tumors. Mol Oncol. 2020; 14(8):1833-1849. PMC: 7400788. DOI: 10.1002/1878-0261.12698. View

20.

Patnaik A, Haluska P, Tolcher A, Erlichman C, Papadopoulos K, Lensing J . A First-in-Human Phase I Study of the Oral p38 MAPK Inhibitor, Ralimetinib (LY2228820 Dimesylate), in Patients with Advanced Cancer. Clin Cancer Res. 2015; 22(5):1095-102. DOI: 10.1158/1078-0432.CCR-15-1718. View