MAP3K1 and MAP2K4 mutations are associated with sensitivity to MEK inhibitors in multiple cancer models

Abstract

Activation of the mitogen-activated protein kinase (MAPK) pathway is frequent in cancer. Drug development efforts have been focused on kinases in this pathway, most notably on RAF and MEK. We show here that MEK inhibition activates JNK-JUN signaling through suppression of DUSP4, leading to activation of HER Receptor Tyrosine Kinases. This stimulates the MAPK pathway in the presence of drug, thereby blunting the effect of MEK inhibition. Cancers that have lost MAP3K1 or MAP2K4 fail to activate JNK-JUN. Consequently, loss-of-function mutations in either MAP3K1 or MAP2K4 confer sensitivity to MEK inhibition by disabling JNK-JUN-mediated feedback loop upon MEK inhibition. In a panel of 168 Patient Derived Xenograft (PDX) tumors, MAP3K1 and MAP2K4 mutation status is a strong predictor of response to MEK inhibition. Our findings suggest that cancers having mutations in MAP3K1 or MAP2K4, which are frequent in tumors of breast, prostate and colon, may respond to MEK inhibitors. Our findings also suggest that MAP3K1 and MAP2K4 are potential drug targets in combination with MEK inhibitors, in spite of the fact that they are encoded by tumor suppressor genes.

Molecular profiles of BRCA1‐associated ovarian cancer treated by platinum‐based therapy: Analysis of primary, residual and relapsed tumors

“…PTCH1 inactivation is frequently observed in basal cell carcinomas. 26 20 All tumor samples obtained from patient OC87 contained p.T405M mutation in the IDH2 gene, which was accompanied by 1p/19q co-deletion.…”

“…25 OC58 contained p.S288P mutation in the kinase domain of MAP2K4 gene; the inhibitors of this molecule are available in laboratory setting. 26…”

Tumor characteristics associated with engraftment of patient‐derived non–small cell lung cancer xenografts in immunocompromised mice

“…7,8 An analysis of the treatment responses of PDXs established from 92 patients with different solid tumors demonstrated a significant association between drug response in patients and the response in mice bearing the corresponding PDXs, indicating that PDXs can predict clinical treatment response. 4 PDX models also are increasingly used in the mechanistic characterization of resistance to targeted therapies, [9][10][11] the identification of novel Cancer November 1, 2019 biomarkers 12 and therapeutic targets, 13 and the characterization of intratumoral heterogeneity. 14,15 Molecular characterization of lung cancer PDXs has demonstrated that these PDXs faithfully retain the genomic alterations found in their corresponding primary tumors.…”

Synthesis and Biological Evaluation of 3‐Arylindazoles as Selective MEK4 Inhibitors

“…Most clinical studies with MEK inhibitors have yielded disappointing results, due at least in part to the paucity of biomarkers of MEK inhibitor sensitivity and toxicity. Bernards and co‐workers recently showed data suggesting that cancers having mutations in MEK4 or its upstream kinase MEKK1, which are frequent in tumors of breast, prostate and colon, may respond to MEK inhibitors . Their findings also suggest that MEKK1 and MEK4 are potential drug targets in combination with current MEK inhibitors, in spite of the fact that they are encoded by putative tumor suppressor genes.…”