In Vivo MAPK Reporting Reveals the Heterogeneity in Tumoral Selection of Resistance to RAF Inhibitors

“Activation of the ERK1/2 mitogen-activated protein kinases (MAPKs) confers resistance to the RAF inhibitors vemurafenib and dabrafenib in mutant BRAF-driven melanomas. Methods to understand how resistance develops are important to optimize the clinical utility of RAF inhibitors in patients. Here we report the development of a novel ERK1/2 reporter system that provides a non-invasive, quantitative and temporal analysis of RAF inhibitor efficacy in vivo. Use of this system revealed heterogeneity in the level of ERK1/2 reactivation associated with acquired resistance to RAF inhibition. We identified several distinct novel and known molecular changes in resistant tumors emerging from treatment-naïve cell populations including BRAF V600E variants and HRAS mutation, both of which were required and sufficient for ERK1/2 reactivation and drug resistance. Our work offers an advance in understanding RAF inhibitor resistance and the heterogeneity in resistance mechanisms, which emerge from a malignant cell population.”

MicroRNA-31 Predicts the Presence of Lymph Node Metastases and Survival in Lung Adenocarcinoma Patients

We performed genome-wide microRNA-sequencing (miRNA-seq) in primary cancer tissue from lung adenocarcinoma patients to identify markers for the presence of lymph node metastasis. MiR-31 was upregulated in lung adenocarcinoma tissues from patients with lymph node metastases compared to those without lymph node metastases. MiR-31 increases cell migration, invasion, and proliferation in an ERK1/2 signaling dependent manner. Low expression of miR-31 is associated with excellent survival for T2N0 patients.

IQGAP1 Scaffold-Kinase Interaction Blockade Selectively Targets RAS-MAP Kinase–Driven Tumors

“Upregulation of the ERK1 and ERK2 (ERK1/2) MAP kinase (MAPK) cascade occurs in >30% of cancers1, often through mutational activation of receptor tyrosine kinases or other upstream genes, including KRAS and BRAF2. Efforts to target endogenous MAPKs are challenged by the fact that these kinases are required for viability in mammals34. Additionally, the effectiveness of new inhibitors of mutant BRAF has been diminished by acquired tumor resistance through selection for BRAF-independent mechanisms of ERK1/2 induction…”

Preclinical Study Indicates Potential for Novel Inhibitor to Overcome Drug Resistance Induced by RAF, MEK Inhibitors

WASHINGTON, D.C. — A new class of investigational medicines may help to treat patients with cancers driven by mutations in genes such as BRAF or KRAS/NRAS, including those patients who have become resistant to therapies that target BRAF directly,…

Selective RAF inhibitor impairs ERK1/2 phosphorylation and growth in mutant NRAS, vemurafenib-resistant melanoma cells

“The RAF inhibitor vemurafenib achieves remarkable clinical responses in mutant BRAF melanoma patients. However, vemurafenib is burdened by acquired drug resistance and by the side effects associated with its paradoxical activation of the ERK1/2 pathway in wild-type BRAF cells. This paradoxical effect has driven the development of a new class of RAF inhibitors. Here, we tested one of these selective, non-paradox-inducing RAF inhibitors termed paradox-breaker-04 (PB04) or PLX7904…”

Activation of ERK1/2 and Akt is associated with cisplatin resistance in human lung cancer cells

Cooperative effects of p-ERK1/2 and p-Akt on attenuating cisplatin cytotoxicity are mediated by PUMA and Bcl-2 regulation, and concurrently blocking these pathways may be an effective strategy for improving the efficacy of cisplatin as anticancer treatment.