202P - eIF4E inhibition exhibits anti-tumor activity and re-sensitizes acquired resistant KRAS G12C NSCLC to KRAS inhibitors

Background

The approval of KRAS^G12C selective inhibitors, sotorasib and adagrasib, marked a critical point in the effort to treat KRAS^G12C mutant NSCLC. Despite the initial clinical benefit observed after treatment, acquired resistance is observed in most patients representing an unmet medical need. eIF4E, a critical regulatory node for multiple oncogenic signaling pathways downstream of KRAS, is a promising target to overcome resistance to KRAS^mut targeted therapies. Many bypass resistance mechanisms to KRAS inhibitors reactivate eIF4E, the main regulator and rate limiting factor for protein synthesis, to promote translation of pro-oncogenic and anti-apoptotic factors including cyclin D1/3, BCL2, and MCL1.

Methods

Here, we present the development of a potent and selective eIF4E inhibitor, RBX-6610, for use in both KRAS^G12C targeted treatment-naïve and resistance settings. RBX-6610 elicits a reversible, dose-dependent cell cycle arrest. However, unlike targeting eIF4A, eIF4E inhibition selectively regulates translation of cancer-dependent pathway proteins instead of global protein synthesis, thus increasing tolerability. Additionally, RBX-6610 demonstrates consistent anti-proliferative effects in sotorasib/adagrasib-naïve and resistant cell lines.

Results

Combining RBX-6610 and KRAS inhibitors in vitro results in the marked increase of caspase3/7 activity and cleaved PARP. The combination treatment not only produces synergistic apoptotic responses in naïve tumor cells but also re-sensitizes resistant cells to KRAS inhibitors. While RBX-6610 monotherapy in vivo causes significant tumor growth inhibition, the combination therapy with sotorasib results in significant tumor regression in a naïve NSCLC xenograft model. A similar in vivo study, performed in a model of sotorasib acquired resistance, is ongoing to validate RBX-6610’s ability to re-sensitize tumor cells to KRAS inhibition.

Conclusions

Collectively, these data support the addition of RBX-6610 to standard of care in both the naïve and treatment resistance settings in KRAS^mut NSCLC patients. IND-enabling studies are planned, marking a significant step toward advancing RBX-6610, a potent eIF4E inhibitor, into the clinic.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

Ribometrix, INC.

Funding

Ribometrix, INC.

Disclosure

A.S. Truong, S.E. Thompson, R.K. Pavana, R.V. Changalvala, J.A. Sorrrentino, M.B. Friedersdorf: Financial Interests, Personal, Full or part-time Employment: Ribometrix, INC.