P3.02-066 Wild-Type KRAS Mediates Growth Inhibition and Resistance to MEK Inhibitors through Dimerization with Mutant KRAS in Lung Adenocarcinoma

Abstract

Mutations in KRAS are the most frequent RAS alterations in human cancers and the prevalent driver event in lung adenocarcinoma (LUAD). There are no effective targeted therapies for KRAS-driven LUAD and chemotherapy remains the standard of care. Small-molecule inhibitors of the MAPK pathway, one of the prominent downstream KRAS mediators, show minimal clinical activity either as single agents or in combination with chemotherapy. Recently, wild-type KRAS (KRASWT) was shown to enhance tumor fitness in KRAS mutant AML and CRC cell lines while concomitantly increasing sensitivity to MEK inhibition. We hypothesized that dimerization between KRAS proteins could be a key regulator for lung adenocarcinoma biology and determinant of treatment response. To study the role of wild-type KRAS in the context of KRAS-driven cancer cells, we used genetically inducible models of KRAS loss of heterozygosity (LOH). We developed an isogenic KRASMUT inducible system that lacks endogenous HRas/NRas but harbors conditional CREERT2-controlled KRaslox alleles. Furthermore, we reconstituted KRASWT and dimerization-deficient KRASD154Q in KRAS-driven murine and human LUAD cell lines lacking the wild-type KRAS allele and evaluated the in vitro and in vivo impact on tumor progression and response to MEK inhibition. KRASWT decreased in vitro and in vivo fitness of human and murine KRAS mutant LUAD tumor cells. However, this phenotype was reverted upon MEK inhibition, with KRAS LOH cells being more sensitive than KRASWT expressing cells. Interestingly, both effects were dependent on wild-type/mutant KRAS dimerization and not observed with the dimerization-deficient KRASD154Q. We provide a mechanistic model of the ambivalent function of KRASWT, linking its tumor suppressor function with increased MEK inhibitor resistance through dimerization with mutant KRAS. KRASWT affects cellular fitness in KRAS-driven LUAD. KRASWT impairs response to MEK inhibitors in KRAS-driven LUAD. KRASWT inhibitory effect is dependent on dimerization with mutant KRAS. Impaired wild-type/mutant KRAS dimerization restores sensitivity to MEK inhibitors in vivo.