Development of MK-8353, an orally administered ERK1/2 inhibitor, in patients with advanced solid tumors

Moschos, Stergios J.; Sullivan, Ryan J.; Hwu, Wen Jen; Ramanathan, Ramesh K.; Adjei, Alex A.; Fong, Peter; Shapira‐Frommer, Ronnie; Tawbi, Hussein Abdul-Hassan; Rubino, Joseph; Rush, Thomas S.; Zhang, Da; Miselis, Nathan R.; Samatar, Ahmed A.; Chun, Patrick Y.; Rubin, Eric H.; Schiller, James E.; Long, Brian J.; Dayananth, Priya; Carr, Donna; Kirschmeier, Paul T.; Bishop, W. Robert; Deng, Yongqi; Cooper, Alan; Shipps, Gerald W.; Moreno, Blanca Homet; Robert, Lídia; Ribas, Antoni; Flaherty, Keith T.

doi:10.1172/jci.insight.92352

Cited by 119 publications

(87 citation statements)

References 31 publications

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“…Resistance to combined BRAF and MEK inhibition is an important clinical challenge in the treatment of metastatic melanoma. ERK inhibitors represent valuable agents currently tested in several clinical trials in melanoma, colorectal, lung, and pancreatic cancers (18,19). The focus of our study was to characterize potential resistance mechanisms to ERKi in melanoma cells using the SCH772984 inhibitor as a model.…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, it induces tumor regression in xenograft models in different cancer types, acts synergistically with VMF to inhibit melanoma cell growth, and delays the onset of acquired resistance (13,14). An oral SCH clinical analogue called MK-8353 and the ATP-competitive ERKi ulixertinib were recently tested in preclinical/phase I stage in patients with advanced solid tumors (18,19). Both agents were well tolerated and displayed reasonable antitumor activity, opening the way for future studies.…”

Section: Introductionmentioning

confidence: 99%

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Resistance to MAPK Inhibitors in Melanoma Involves Activation of the IGF1R–MEK5–Erk5 Pathway

et al. 2019

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Combined treatment of metastatic melanoma with BRAF and MEK inhibitors has improved survival, but the emergence of resistance represents an important clinical challenge. Targeting ERK is a suitable strategy currently being investigated in melanoma and other cancers. To anticipate possible resistance to ERK inhibitors (ERKi), we used SCH772984 (SCH) as a model ERKi to characterize resistance mechanisms in two BRAF V600E melanoma cell lines. The ERKi-resistant cells were also resistant to vemurafenib (VMF), trametinib (TMT), and combined treatment with either VMF and SCH or TMT and SCH. Resistance to SCH involved stimulation of the IGF1R-MEK5-Erk5 signaling pathway, which counteracted inhibition of Erk1/2 activation and cell growth. Inhibition of IGF1R with linsitinib blocked Erk5 activation in SCH-resistant cells and decreased their growth in 3D spheroid growth assays as well as in NOD scid gamma (NSG) mice. Cells doubly resistant to VMF and TMT or to VMF and SCH also exhibited downregulated Erk1/2 activation linked to stimulation of the IGF1R-MEK5-Erk5 pathway, which accounted for resistance. In addition, we found that the decreased Erk1/2 activation in SCH-resistant cells involved reduced expression and function of TGFa. These data reveal an escape signaling route that melanoma cells use to bypass Erk1/2 blockade during targeted melanoma treatment and offer several possible targets whose disruption may circumvent resistance. Significance: Activation of the IGF1R-MEK5-Erk5 signaling pathway opposes pharmacologic inhibition of Erk1/2 in melanoma, leading to the reactivation of cell proliferation and acquired resistance.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Resistance to MAPK Inhibitors in Melanoma Involves Activation of the IGF1R–MEK5–Erk5 Pathway

et al. 2019

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“…ERK inhibitors have demonstrated efficacy in preclinical cancer models, including those resistant to BRAF or MEK inhibitors (20)(21)(22)(23). More recently, other ERK inhibitors have demonstrated clinical activity in patients with BRAF V600-mutant melanoma who were either refractory or na€ ve to BRAF and MEK inhibitor combination therapy (24,25). However, the potential value of ERK inhibitors expands beyond melanoma and acquired resistance in melanoma to target all cancers with ERK pathway alterations.…”

Section: Introductionmentioning

confidence: 99%

ERK Inhibitor LY3214996 Targets ERK Pathway–Driven Cancers: A Therapeutic Approach Toward Precision Medicine

Bhagwat

McMillen

Cai

et al. 2020

Molecular Cancer Therapeutics

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The ERK pathway is critical in oncogenesis; aberrations in components of this pathway are common in approximately 30% of human cancers. ERK1/2 (ERK) regulates cell proliferation, differentiation, and survival and is the terminal node of the pathway. BRAF-and MEK-targeted therapies are effective in BRAF V600E/K metastatic melanoma and lung cancers; however, responses are short-lived due to emergence of resistance. Reactivation of ERK signaling is central to the mechanisms of acquired resistance. Therefore, ERK inhibition provides an opportunity to overcome resistance and leads to improved efficacy. In addition, KRAS-mutant cancers remain an unmet medical need in which ERK inhibitors may provide treatment options alone or in combination with other agents. Here, we report identification and activity of LY3214996, a potent, selective, ATP-competitive ERK inhibitor. LY3214996 treatment inhibited the pharmacodynamic biomarker, phospho-p90RSK1, in cells and tumors, and correlated with LY3214996 exposures and antitumor activities. In in vitro cell proliferation assays, sensitivity to LY3214996 correlated with ERK pathway aberrations. LY3214996 showed dose-dependent tumor growth inhibition and regression in xenograft models harboring ERK pathway alterations. Importantly, more than 50% target inhibition for up to 8 to 16 hours was sufficient for significant tumor growth inhibition as single agent in BRAFand KRAS-mutant models. LY3214996 also exhibited synergistic combination benefit with a pan-RAF inhibitor in a KRAS-mutant colorectal cancer xenograft model. Furthermore, LY3214996 demonstrated antitumor activity in BRAF-mutant models with acquired resistance in vitro and in vivo. Based on these preclinical data, LY3214996 has advanced to an ongoing phase I clinical trial (NCT02857270).

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“…Several selective inhibitors of ERK signaling are reported to have marked antitumor efficacy, including FR180204 [28], BVD523 [29], CC90003 [30], GDC-0994 [31] and MK-8353 [32]. BVD523 (Ulixertinib) specifically has been used in clinical trials, showing clear efficacy in patients who have been previously treated with immunotherapy [29].…”

Section: Mek/erk Inhibitionmentioning

confidence: 99%

Mitogen-Activated Protein Kinase Inhibitors and T-Cell-Dependent Immunotherapy in Cancer

et al. 2020

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Mitogen-activated protein kinase (MAPK) signaling networks serve to regulate a wide range of physiologic and cancer-associated cell processes. For instance, a variety of oncogenic mutations often lead to hyperactivation of MAPK signaling, thereby enhancing tumor cell proliferation and disease progression. As such, several components of the MAPK signaling network have been proposed as viable targets for cancer therapy. However, the contributions of MAPK signaling extend well beyond the tumor cells, and several MAPK effectors have been identified as key mediators of the tumor microenvironment (TME), particularly with respect to the local immune infiltrate. In fact, a blockade of various MAPK signals has been suggested to fundamentally alter the interaction between tumor cells and T lymphocytes and have been suggested a potential adjuvant to immune checkpoint inhibition in the clinic. Therefore, in this review article, we discuss the various mechanisms through which MAPK family members contribute to T-cell biology, as well as circumstances in which MAPK inhibition may potentiate or limit cancer immunotherapy.

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Development of MK-8353, an orally administered ERK1/2 inhibitor, in patients with advanced solid tumors

Abstract: Merck Sharp & Dohme Corp., a subsidiary of Merck & Co. Inc., and NIH (P01 CA168585 and R35 CA197633).

Cited by 119 publications

References 31 publications

Resistance to MAPK Inhibitors in Melanoma Involves Activation of the IGF1R–MEK5–Erk5 Pathway

Resistance to MAPK Inhibitors in Melanoma Involves Activation of the IGF1R–MEK5–Erk5 Pathway

ERK Inhibitor LY3214996 Targets ERK Pathway–Driven Cancers: A Therapeutic Approach Toward Precision Medicine

Mitogen-Activated Protein Kinase Inhibitors and T-Cell-Dependent Immunotherapy in Cancer

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