KRAS^G12C inhibition using MRTX1257: a novel radio-sensitizing partner

KRAS activating mutations are considered the most frequent oncogenic drivers and are correlated with radio-resistance in multiple cancers including non-small cell lung cancer (NSCLC) and colorectal cancer. Although KRAS was considered undruggable until recently, several KRAS inhibitors have recently reached clinical development. Among them, MRTX849 (Mirati Therapeutics) showed encouraging clinical outcomes for the treatment of selected patients with KRAS^G12C mutated NSCLC and colorectal cancers. In this work, we explore the ability of MRTX1257, a KRAS^G12C inhibitor analogous to MRTX849, to radio-sensitize KRAS^G12C+/+ mutated cell lines and tumors.

Both in vitro and in vivo models of radiotherapy (RT) in association with MRTX1257 were used, with different RAS mutational profiles. We assessed in vitro the radio-sensitizing effect of MRTX1257 in CT26 KRAS^G12C+/+, CT26 WT, LL2 WT and LL2 NRAS KO (LL2 NRAS^-/-) cell lines. In vivo, we used syngeneic models of subcutaneous CT26 KRAS^G12C+/+ tumors in BALB/c mice and T cell deficient athymic nu/nu mice to assess both the radio-sensitizing effect of MRTX1257 and its immunological features.

MRTX1257 was able to radio-sensitize CT26 KRAS^G12C+/+ cells in vitro in a time and dose dependent manner. Moreover, RT in association with MRTX1257 in BALB/c mice bearing CT26 KRAS^G12C+/+ subcutaneous tumors resulted in an observable cure rate of 20%. However, no durable response was observed with similar treatment in athymic nude mice. The analysis of the immune microenvironment of CT26 KRAS^G12C+/+ tumors following RT and MRTX1257 showed an increase in the proportion of various cell subtypes including conventional CD4 + T cells, dendritic cells type 2 (cDC2) and inflammatory monocytes. Furthermore, the expression of PD-L1 was dramatically down-regulated within both tumor and myeloid cells, thus illustrating the polarization of the tumor microenvironment towards a pro-inflammatory and anti-tumor phenotype following the combined treatment.

This work is the first to demonstrate in vitro as in vivo the radio-sensitizing effect of MRTX1257, a potent KRAS^G12C inhibitor compatible with oral administration, in CT26 KRAS^G12C mutated cell lines and tumors. This is a first step towards the use of new combinatorial strategies using KRAS inhibitors and RT in KRAS^G12C mutated tumors, which are the most represented in NSCLC with 14% of patients harboring this mutational profile.