Aberrant activation of signaling through the RAS-RAF-MEK-ERK (MAPK) pathway is implicated in numerous cancers, making it an attractive therapeutic target. Although BRAF and MEK-targeted combination therapy has demonstrated significant benefit beyond single-agent options, the majority of patients develop resistance and disease progression after approximately 12 months. Reactivation of ERK signaling is a common driver of resistance in this setting. Here we report the discovery of BVD-523 (ulixertinib), a novel, reversible, ATP-competitive ERK1/2 inhibitor with high potency and ERK1/2 selectivity. In vitro BVD-523 treatment resulted in reduced proliferation and enhanced caspase activity in sensitive cells. Interestingly, BVD-523 inhibited phosphorylation of target substrates despite increased phosphorylation of ERK1/2. In in vivo xenograft studies, BVD-523 showed dose-dependent growth inhibition and tumor regression. BVD-523 yielded synergistic antiproliferative effects in a BRAF V600E -mutant melanoma cell line xenograft model when used in combination with BRAF inhibition. Antitumor activity was also demonstrated in in vitro and in vivo models of acquired resistance to singleagent and combination BRAF/MEK-targeted therapy. On the basis of these promising results, these studies demonstrate BVD-523 holds promise as a treatment for ERK-dependent cancers, including those whose tumors have acquired resistance to other treatments targeting upstream nodes of the MAPK pathway. Assessment of BVD-523 in clinical trials is underway

Platinum-based DNA-damaging chemotherapy is standard-of-care for most patients with lung cancer but outcomes remain poor. This has been attributed, in part, to the highly effective repair network known as the DNA-damage response (DDR). ATR kinase is a critical regulator of this pathway, and its inhibition has been shown to sensitize some cancer, but not normal, cells in vitro to DNA damaging agents. However, there are limited in vivo proof-of-concept data for ATR inhibition. To address this we profiled VX-970, the first clinical ATR inhibitor, in a series of in vitro and in vivo lung cancer models and compared it with an inhibitor of the downstream kinase Chk1. VX-970 markedly sensitized a large proportion of a lung cancer cell line and primary tumor panel in vitro to multiple DNA damaging drugs with clear differences to Chk1 inhibition observed. In vivo VX-970 blocked ATR activity in tumors and dramatically enhanced the efficacy of cisplatin across a panel of patient derived primary lung xenografts. The combination led to complete tumor growth inhibition in three cisplatin-insensitive models and durable tumor regression in a cisplatin-sensitive model. These data provide a strong rationale for the clinical evaluation of VX-970 in lung cancer patients.

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Chromosome instability (CIN) is deleterious to normal cells because of the burden of aneuploidy. However, most human solid tumors have an abnormal karyotype implying that gain and loss of chromosomes by cancer cells confers a selective advantage. CIN can be induced in the mouse by inactivating the spindle assembly checkpoint. This is lethal in the germline but we show here that adult T cells and hepatocytes can survive conditional inactivation of the Mad2l1 SAC gene and resulting CIN. This causes rapid onset of acute lymphoblastic leukemia (T-ALL) and progressive development of hepatocellular carcinoma (HCC), both lethal diseases. The resulting DNA copy number variation and patterns of chromosome loss and gain are tumor-type specific, suggesting differential selective pressures on the two tumor cell types.DOI: http://dx.doi.org/10.7554/eLife.20873.001

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The synthesis and characterization of a novel polycyclic azaindole based derivative is disclosed, and its binding to JAK2 is described. The compound is further evaluated for its ability to block the EPO/JAK2 signaling cascade in vitro and in vivo.

The MAPK (RAS-RAF-MEK-ERK) pathway is activated in many cancers, and the clinical efficacy of BRAF and MEK inhibitors in melanoma confirms that targeting the MAPK pathway has therapeutic potential. Unfortunately, intrinsic and acquired drug resistance limits use of MAPK-directed therapies, and resistance is often associated with activated ERK signaling. Here, we report characterization of BVD-523 (ulixertinib), a novel small-molecule ERK1/2 kinase inhibitor currently under investigation in Phase 1 clinical trials. BVD-523 potently and selectively inhibits ERK1 and ERK2 kinases in a reversible, ATP-competitive fashion. Consistent with its mechanism of action, BVD-523 inhibits signal transduction, cell proliferation, and cell survival, most potently in cell lines bearing mutations that activate MAPK pathway signaling. Similarly, single-agent BVD-523 inhibits tumor growth in vivo in BRAF-mutant melanoma and colorectal xenografts as well as in KRAS-mutant colorectal and pancreatic models. Combination treatment with BVD-523 and dabrafenib inhibits tumor growth in a BRAF-mutant melanoma model. Importantly, BVD-523 is effective in several models that show intrinsic or acquired resistance to other MAPK pathway inhibitors. BVD-523 inhibits with equivalent potency the growth of parental cells or those cultured for resistance to dabrafenib, trametinib, or the combination of both drugs. Additionally, BVD-523 inhibits growth in wild-type cells and a RAF/MEK cross-resistant cell line bearing a MEK1 Q56P mutation with similar potency. Lastly, single-agent BVD-523 inhibits the growth of a patient-derived tumor xenograft harboring cross-resistance to dabrafenib, trametinib, and the combination treatment following clinical progression on a MEK inhibitor. Phase 1 trials of BVD-523 are currently recruiting patients with advanced solid tumors (NCT0178429) or hematologic malignancies (NCT02296242). Eligibility criteria include diagnosis according to certain genetic features, and treatment in backgrounds including progression following prior MAPK targeted therapy. The primary objective of these studies is to identify the recommended Phase 2 dose(s) for single-agent BVD-523 treatment. Additional objectives include pharmacokinetic and pharmacodynamic assessments, and preliminary measures of efficacy. The solid tumor protocol has met its study objectives in Part 1 (defining the safety profile and maximum tolerated dose), and will be reported separately; findings appear consistent with the activity profile defined in preclinical studies. In total, preclinical and clinical studies will help elucidate how BVD-523 (ulixertinib) may be used as a novel agent in MAPK-directed therapeutic strategies, including for patients that have failed treatment due to intrinsic or acquired resistance and active signaling through ERK. Citation Format: Ursula Germann, Brinley Furey, Jeff Roix, William Markland, Russell Hoover, Alex Aronov, Michael Hale, Guanjing Chen, Gabriel Martinez-Botella, Rossitza Alargova, Bin Fan, David Sorrell, Kay Meshaw, Paul Shapiro, Michael J. Wick, Cyril Benes, Mathew Garnett, Gary DeCrescenzo, Mark Namchuk, Saurabh Saha, Dean J. Welsch. The selective ERK inhibitor BVD-523 is active in models of MAPK pathway-dependent cancers, including those with intrinsic and acquired drug resistance. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4693. doi:10.1158/1538-7445.AM2015-4693