Oncogenic KRAS is dependent upon an EFR3A-PI4KA signaling axis for potent tumorigenic activity

Hema Adhikari,John F Hancock,Shivesh Kumar,Pei Zhou,Walaa E Kattan,Christopher M Counter

doi:10.1038/s41467-021-25523-5

Abstract

The HRAS, NRAS, and KRAS genes are collectively mutated in a fifth of all human cancers. These mutations render RAS GTP-bound and active, constitutively binding effector proteins to promote signaling conducive to tumorigenic growth. To further elucidate how RAS oncoproteins signal, we mined RAS interactomes for potential vulnerabilities. Here we identify EFR3A, an adapter protein for the phosphatidylinositol kinase PI4KA, to preferentially bind oncogenic KRAS. Disrupting EFR3A or PI4KA reduces phosphatidylinositol-4-phosphate, phosphatidylserine, and KRAS levels at the plasma membrane, as well as oncogenic signaling and tumorigenesis, phenotypes rescued by tethering PI4KA to the plasma membrane. Finally, we show that a selective PI4KA inhibitor augments the antineoplastic activity of the KRASG12C inhibitor sotorasib, suggesting a clinical path to exploit this pathway. In sum, we have discovered a distinct KRAS signaling axis with actionable therapeutic potential for the treatment of KRAS-mutant cancers.

Highlights

The HRAS, NRAS, and KRAS genes are collectively mutated in a fifth of all human cancers
Focusing on KRAS, as it is the most commonly mutated of the three RAS genes in human cancers[1], we further show that that loss of EFR3A/B or PI4KA reduces the levels of PI(4)P and PS, as well as KRAS localization and nanoclustering at the plasma membrane
EFR3A appears to form a unique positive-feedback circuit whereby activated RAS binds EFR3A, which in turn promotes signaling by the oncoprotein. Such a circuit opens up the possibility of pharmacologically augmenting the antineoplastic activity of RAS inhibitors with PI4KA inhibitors, and in agreement, we demonstrate that a selective PI4KA inhibitor is synergistic with the clinical KRASG12C inhibitor sotorasib

Summary

Introduction

The HRAS, NRAS, and KRAS genes are collectively mutated in a fifth of all human cancers These mutations render RAS GTP-bound and active, constitutively binding effector proteins to promote signaling conducive to tumorigenic growth. We identify EFR3A, an adapter protein for the phosphatidylinositol kinase PI4KA, to preferentially bind oncogenic KRAS. 1234567890():,; The three RAS genes HRAS, NRAS, and KRAS are collectively mutated in a fifth of human cancers[1]. These mutations primarily alter residues G12, G13, or Q612, which leave RAS in a constitutively active and oncogenic GTP-bound state[3]. PI4KA is recruited to plasma membrane by the adapter protein EFR327,28, which has two isoforms, EFR3A and EFR3B29.

Methods

Results

Conclusion