COT/MAP3K8 drives resistance to RAF inhibition through MAP kinase pathway reactivation

By Cory M. Johannessen, J. Boehm, S. Kim, S. Thomas, Leslie H. Wardwell, L. Johnson, Caroline M. Emery, Nicolas Stransky, Alexandria P. Cogdill, J. Barretina and 25 more. Nature, 2010

731 citations recorded by the source corpus.

Oncogenic mutations in the serine/threonine kinase B-RAF (also known as BRAF) are found in 50–70% of malignant melanomas. Pre-clinical studies have demonstrated that the B-RAF(V600E) mutation predicts a dependency on the mitogen-activated protein kinase (MAPK) signalling cascade in melanoma—an observation that has been validated by the success of RAF and MEK inhibitors in clinical trials. However, clinical responses to targeted anticancer therapeutics are frequently confounded by de novo or acquired resistance. Identification of resistance mechanisms in a manner that elucidates alternative ‘druggable’ targets may inform effective long-term treatment strategies. Here we expressed ∼600 kinase and kinase-related open reading frames (ORFs) in parallel to interrogate resistance to a selective RAF kinase inhibitor. We identified MAP3K8 (the gene encoding COT/Tpl2) as a MAPK pathway agonist that drives resistance to RAF inhibition in B-RAF(V600E) cell lines. COT activates ERK primarily through MEK-dependent mechanisms that do not require RAF signalling. Moreover, COT expression is associated with de novo resistance in B-RAF(V600E) cultured cell lines and acquired resistance in melanoma cells and tissue obtained from relapsing patients following treatment with MEK or RAF inhibitors. We further identify combinatorial MAPK pathway inhibition or targeting of COT kinase activity as possible therapeutic strategies for reducing MAPK pathway activation in this setting. Together, these results provide new insights into resistance mechanisms involving the MAPK pathway and articulate an integrative approach through which high-throughput functional screens may inform the development of novel therapeutic strategies.

Subfields: Computational Theory and Mathematics, Molecular Biology, Oncology

View Paper: https://www.semanticscholar.org/paper/b63f4ce7fd4aa7aabf622beb5c8f3e8e754d5920

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In Computational Theory and Mathematics

1. Walter Kolch

In Molecular Biology

1. M. Bahar
2. D. Kim
3. Hyun Joon Kim
4. Walter Kolch
5. S. Morrison
6. C. Sawyers
7. C. Hill
8. Bernhard Schmierer

In Oncology

1. Walter Kolch
2. S. Morrison
3. Jeffrey A. Magee
4. C. Sawyers
5. E. Piskounova
6. E. Scholar
7. A. Arora

Citations in the corpus

• Lessons from the cancer genome. (2013, neutral): “Multiple genetic mechanisms of resistance have been described (oncogenicNRASmutations, COT/MAP3K8 gains,BRAF amplification, activatingMEK1mutations, and NF1 loss), each of which produces sustained MAP kinase (ERK) activity in the presence of drug (Emery et al., 2009; Johannessen et al., 2010; Nazari”
• Glucocorticoid Receptor Confers Resistance to Anti-Androgens by Bypassing Androgen Receptor Blockade (2013, positive): “…bypass model of AR pathway blockade reported here is reminiscent of recent reports that kinase inhibitor blockade in various cancers can be overcome by upregulation of other kinases and/or their ligands (Engelman et al., 2007; Johannessen et al., 2010; Straussman et al., 2012; Wilson et al., 2012).”
• Cancer stem cells: impact, heterogeneity, and uncertainty. (2012, background): “Melanomas carrying V600E BRAF mutations become resistant to the BRAF inhibitor vemurafenib through a variety of genetic mechanisms (Johannessen et al., 2010; Nazarian et al., 2010; Poulikakos et al., 2011; Poulikakos and Rosen, 2011; Villanueva et al., 2010), and we are unable to find any evidence…”
• Targeting the RAS/RAF/MAPK pathway for cancer therapy: from mechanism to clinical studies (2023, background): “370,371 Adaptive RAFi resistance .”
• Targeting MAPK Signaling in Cancer: Mechanisms of Drug Resistance and Sensitivity (2020, background): “Vemurafenib Selective BRAF V600E inhibitor (ATP competitive) Activating mutations in NRAS or MEK [23,24]; BRAF/CRAF amplification [23,25]; BRAF alternative splicing [26,27]; RAF heterodimerization [28]; RTK upregulation [29]; Loss of NF1 [30]; COT upregulation [31] Dabrafenib”