Dual CDK4/6, MEK Blockade Demonstrates Synergy in PNET Models

Combination CDK4/6 and MEK inhibition was “highly synergistic” in killing pancreatic neuroendocrine tumor (PNET) cells in vitro and effectively suppressed PNET growth in mice, suggesting the viability of the approach in patients with tumors that harbor activated MEK and CDK4/6 according to Ume Salma Shaik Amjad, PhD.¹

Treatment with the investigational MEK inhibitor mirdametinib and CDK4/6 inhibitor palbociclib (Ibrance) led to cell arrest and cell death in cultured BON-1 PNET cells.¹ “Using low-dose combinations of both drugs, we validated that the drugs act synergistically on the target RB1 [retinoblastoma] by greatly reducing its phosphorylation. The combination of CDK and MEK also synergistically reduced the long-term growth of PNETs, [leading to] fewer and smaller colonies,” Shaik Amjad said during a presentation at the North American Neuroendocrine Tumor Society 2020 Annual Symposium.

“Most excitingly, [the dual-drug approach] was highly effective in vivo,” added Shaik Amjad, an assistant research scientist in the Dawn Quelle Laboratory in the department of neuroscience and pharmacology at the University of Iowa Carver College of Medicine in Iowa City. In PNET-carrying BON-1 xenograft models, mirdametinib and palbociclib monotherapy “modestly” slowed growth compared with controls, whereas the combination resulted in a “6-fold extension in survival.”¹

The findings support further analyses of combined CDK and MEK inhibition in PNETs, and several investigators have already begun testing the efficacy of mirdametinib and palbociclib in other model systems, including patient-derived NET spheroids, where “encouraging evidence of synergy” has been seen, Shaik Amjad said. Further, Shaik Amjad et al will also evaluate the doublet therapy in in vivo PNET patient-derived xenograft models and in vivo immune competent PNET mouse models “to determine if the combination is more active in an immune competent setting,” while exploring mechanisms of resistance to the regimen.¹

Mirametinib is a small molecule designed to inhibit MEK1 and MEK2. The experimental agent is currently being evaluated in neurofibromatosis type 1-associated plexiform neurofibromas and its developer, SpringWorks Therapetics Inc, also plans to explore its efficacy across a range of solid tumors.² Palbociclib is a CDK4/6–directed therapy first approved conditionally in conjunction with letrozole in February 2015 for estrogen receptor-positive, HER2-negative advanced breast cancer as initial endocrine-based therapy in postmenopausal women.³

Hypothesizing Efficacy

The rationale to test dual CDK4/6 and MEK inhibition in PNETs stems from a lack of single-agent efficacy in this space, Shaik Amjad explained. A variety of kinase inhibitors have been investigated in PNETs, including: everolimus (Afinitor), temisirolimus (Torisel), sunitinib (Sutent), pazopanib (Votrient), cabozantinib (Cabometyx), sorafenib (Nexavar), ribociclib (Kisqali) and palbociclib.¹

“Unfortunately, none of these therapies has improved overall survival, requiring the development of more effective combination therapies that promote tumor arrest and/or regression,” Shaik Amjad said.

Although CDK4/6 inhibitor monotherapy has been the focus of several PNET-focused studies, the modality has failed to not only boost overall survival, but also progression-free survival, Shaik Ahmad said. This clinical reality, coupled with Shaik Amjad and colleagues’ discovery of a new essential oncogenic driver of PNETs, RABL6A, guided their decision to pair an anti–CDK4/6 agent with a MEK inhibitor.¹

RABL6A is a marker of poor survival in pancreatic ductal adenocarcinoma and breast cancer and is notably overexpressed and hyperactivated in advanced PNETs. The driver is required for malignant cell proliferation in vitro and also promotes tumor growth in vivo. RABL6A specifically supports cell proliferation and survival through multiple pathways, and successfully suppresses the RB1 tumor suppressor via CDK activation. Quantitative kinome and phosphoproteome of PNET cells showed that RABL6A is necessary to activate many tumor-assisting kinases, including CDKs and MEK1/2.¹

Shaik Amjad et al’s finding that the CDK and MEK kinases are activated by RABL6A has 2 clinical implications, she said. The first, in accordance with existing evidence from Scott et al, is that it is likely that patient’s tumors do indeed express hyperactive CDK and MEK kinases. The second implication is that combining CDK4/6 blockade with MEK inhibition could synergistically reactive the RB1 tumor suppressor, potentially leading to improved outcomes in patients with PNETs.¹

“We were very interested in targeting both CDK and MEK because recent studies showed remarkable benefits of combined MEK [inhibitors], like trametinib and mirdametinib with CDK4/6 inhibitors like palbociclib since they synergize to fully activate the RB1 tumor suppressor and induce tumor stasis through senescence,” Shaik Amjad said. When coadministered, CDK– and MEK–directed agents can also modulate T-cell function and tumor infiltration, further contributing to their appeal, she concluded.¹

References:

1. Shaik Amjad US, Kaemmer CA, Maharjan CK, et al. Efficacy of combined MEK and CDK targeted therapies for pancreatic neuroendocrine tumors. Poster presented at: North American Neuroendocrine Tumor Society 2020 Annual Symposium; October 2-3, 2020; virtual. Abstract B-13.
2. SpringWorks Therapeutics announces initiation of phase 2b ReNeu clinical trial of mirdametinib in children and adults with neurofibromatosis type 1 (NF1)-associated plexiform neurofibromas (NF1-PN). News release. SpringWorks Therapeutics, Inc. October 24, 2019. Accessed October 2, 2020. https://bit.ly/3irzqMk
3. Palbociclib (Ibrance). FDA. March 31, 2017. Accessed October 2, 2020. https://www.fda.gov/drugs/resources-information-approved-drugs/palbociclib-ibrance