Sensitivity and Resistance of Oncogenic RAS-Driven Tumors to Dual MEK and ERK Inhibition

Abstract

Oncogenic mutations in RAS family genes arise frequently in metastatic human cancers. Here we developed new mouse and cellular models of oncogenic HrasG12V-driven undifferentiated pleomorphic sarcoma metastasis and of KrasG12D-driven pancreatic ductal adenocarcinoma metastasis. Through analyses of these cells and of human oncogenic KRAS-, NRAS- and BRAF-driven cancer cell lines we identified that resistance to single MEK inhibitor and ERK inhibitor treatments arise rapidly but combination therapy completely blocks the emergence of resistance. The prior evolution of resistance to either single agent frequently leads to resistance to dual treatment. Dual MEK inhibitor plus ERK inhibitor therapy shows anti-tumor efficacy in an HrasG12V-driven autochthonous sarcoma model but features of drug resistance in vivo were also evident. Array-based kinome activity profiling revealed an absence of common patterns of signaling rewiring in single or double MEK and ERK inhibitor resistant cells, showing that the development of resistance to downstream signaling inhibition in oncogenic RAS-driven tumors represents a heterogeneous process. Nonetheless, in some single and double MEK and ERK inhibitor resistant cell lines we identified newly acquired drug sensitivities. These may represent additional therapeutic targets in oncogenic RAS-driven tumors and provide general proof-of-principle that therapeutic vulnerabilities of drug resistant cells can be identified.

The Genomic, Transcriptomic, and Immunologic Landscape of HRAS Mutations in Solid Tumors

“…Murine models have demonstrated activity of MEK inhibition alone in other HRASmt diseases, such as Costello syndrome [52]. Finally, mTOR inhibitors combined with ERK inhibition demonstrated activity against HRASmt G12V-driven autochthonous sarcoma [53]. Given the current approval of everolimus in the advanced/metastatic HR+ BC setting [54], future analyses may consider determining if HRASmt cancers serve as a predictor of response.…”

Mapping the Protein Kinome: Current Strategy and Future Direction

“…The results suggested that Akt and p53 might be potential host therapeutic targets [ 46 ]. Array-based kinome profiling revealed that signals were rewired in resistant cells, and the results were confirmed by Western blots [ 47 ]. Furthermore, signaling pathways with spatial resolution have been achieved by analyzing the kinome in subcellular partitioning [ 48 ].…”

Recent Developments in Targeting RAS Downstream Effectors for RAS-Driven Cancer Therapy

“…Similarly, Catalano et al showed that dual inhibition of MEK and Erk represented anti-tumor efficacy and blocked the emergence of drug resistance in an HRAS G12C -driven autochthonous sarcoma model. However, this combination could not be successful to revert previously developed resistance, which offers the use of dual MEK and Erk treatment as a first-line therapy [140]. In addition to these, the authors noted that some cell lines resistant to combined MEK and Erk inhibition showed dependency on MAP4K4 activity, which serves MAP4K4 as a potential new therapeutic target [140].…”

“…However, this combination could not be successful to revert previously developed resistance, which offers the use of dual MEK and Erk treatment as a first-line therapy [140]. In addition to these, the authors noted that some cell lines resistant to combined MEK and Erk inhibition showed dependency on MAP4K4 activity, which serves MAP4K4 as a potential new therapeutic target [140]. Despite these successful examples of dual MEK and Erk inhibition in some RAS-mutant models, the potential of these combinations for clinical implementation awaits further investigation.…”