MRTX1257

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

MRTX1257 predominantly reduced proliferation of XG7 cells, whereas MRTX1133 led to potent cell death induction of KARPAS620 and KP6 cells. Combinations of MRTX1257 with investigational or established anti-MM drugs, including melphalan, bortezomib or pomalidomide, led to no antagonism and in some cases – including combination with MEKi trametinib – caused supra-additive effects... This study documents mutant-specific activity of KRAS G12C and G12D inhibitors in MM cells and provides functional insights into the pharmacological inhibition of KRAS in MM. Ongoing in vitro and in vivo studies are examining the targeting of genes/pathways associated with escape from KRAS inhibition, as a framework for future efforts to improve the rates, depth and durability of responses to KRAS inhibition in MM.

Legal entity responsible for the study The authors. Expression of PD-L1 was reduced within tumor and myeloid cells, illustrating TME polarization towards a pro-inflammatory phenotype following the combination. Conclusions This work constitutes a first step towards new combinatorial approaches involving RT and MRTX1257 in KRAS G12C mutated cancers, with the aim of providing new therapeutic strategies.

The three lines exhibit similar in vitro sensitivities to KRAS inhibitors (MRTX-1257, MRTX-849, AMG-510), but distinct in vivo responses to MRTX-849 ranging from progressive growth with orthotopic LLC-NRAS KO tumors to modest shrinkage with mKRC.1 tumors. All three cell lines exhibited synergistic in vitro growth inhibition with combinations of MRTX-1257 and the SHP2/PTPN11 inhibitor, RMC-4550...Notably, single-agent MRTX-849 activity in mKRC.1 tumors and the combination response in LLC-NRAS KO tumors was lost when the experiments were performed in athymic nu/nu mice, supporting a growing literature demonstrating a role for adaptive immunity in the response to this class of drugs. These new models of murine KRAS mutant lung cancer should prove valuable for identifying improved therapeutic combination strategies with KRAS inhibitors.

FDA has recently granted approval to sotorasib for KRAS G12C mutated non-small cell lung cancer (NSCLC)...In this study, combining nuclear transport inhibitor selinexor with KRAS G12C inhibitors has resulted in potent antitumor effects in preclinical cancer models. This can be an effective combination therapy for cancer patients that do not respond or develop resistance to KRAS G12C inhibitor treatment.

The approved and investigational agents were selected to target specific genetic variants and pathways: KRAS G12C covalent inhibitors (sotorasib and MRTX-1257), RAS pathway inhibitors (BAY-293, BI-3406 and TNO-155), BRAF V600E/K inhibitors (dabrafenib and encorafenib), ABCB1 substrates (paclitaxel, doxorubicin, 5-FU, AZD-1775, and SN-38), and ABCB1 non-substrates (gemcitabine and trametinib)...This project was funded in part with federal funds from the NCI, NIH, under contract no. HHSN261201500003I.

The most successful combination was TNO-155 plus ipatasertib which resulted in more than 1-log of cell kill in 9 of 20 lines including the 5 KRAS G12C mutant lines. Venetoclax in combination with the RAS pathway inhibitors was active in 4 of the 5 KRAS G12C lines as was the combination of sapanisertib and TNO-155...This project was funded in part with federal funds from the NCI, NIH, under contract no. HHSN261200800001E.

In this study, we have tested two potent KRASG12C inhibitors, MRTX1257 and AMG510, on PDAC and NSCLC cell lines both as single agents and also in combination with nuclear transport inhibitor, Selinexor (KPT-330/XPOVIO). Cell growth inhibition was determined by MTT assay. In conclusion, we have demonstrated that the inhibitor of nuclear transport protein XPO1 has the ability to potentiate the anticancer activity of KRASG12C inhibitors in in vitro preclinical models of PDAC and NSCLC.

The pancreatic cancer cell line 323965-272-R-J2 carrying a KRASG12C variant exhibited an enhanced sensitivity to the combination of the mTOR inhibitor everolimus and a low concentration of either AMG-510 or MRTX-1257...Similarly, combining the mTOR kinase inhibitor sapanisertib, which blocks both mTORC1 and mTORC2 activities, with MTRX-1257 also led to a notable reduction in cell viability in all three KRASG12C-containing cell lines. In the KRASG12C variant melanoma cell line 299254-011-R-J1, targeting of the upstream receptor tyrosine kinase FGFR with erdafitinib in combination with the KRASG12C inhibitors produced greater than additive cell killing over the concentration range from 0.1 to 10 µM. Lastly, both KRASG12C inhibitors and abemaciclib, demonstrated additive to greater than additive cytotoxicity in the pancreatic cancer cell line 323965-272-R-J2, but this outcome was not observed with the CDK4/6 inhibitor, palbociclib, or in the other KRASG12C variant cell lines. These preclinical findings provide guidance regarding selection of combination regimens with KRASG12C inhibitors that may result in increased clinical efficacy.

AMG 510 and the IS (MRTX-1257) were extracted from mouse plasma using tert-butyl methyl ether and chromatographed using an isocratic mobile phase (0.2% formic acid:acetonitrile; 25:75, v/v) at a flow-rate of 0.65 mL/min on an Atlantis dC column. AMG 510 was demonstrated to be stable under the tested storage conditions. This novel method has been applied to a pharmacokinetic study in mice.

C57BL/6J mice bearing established KP4662-G12C (KRASG12C/TP53R172H/+) tumors (at least 150 mm3) were treated as indicated: A1421 (CD73i; 30 mg/kg/day, s.c.), anti-PD1 (Clone RMP 1-14; 10 mg/kg; twice per week, i.p), and MRTX-1257 (KRASi, 100 mg/kg/day, p.o.)... Here, we show that direct inhibition of mutant KRAS in pancreatic cancer models yields complex immunomodulatory effects. While antigen presentation pathways are transcriptionally upregulated and the expression of immunosuppressive chemokine is reduced, KRAS inhibition also reprograms nucleotide metabolism leading to elevated levels of ADO. These findings suggest that co-targeting mutant KRAS and adenosine signaling may enhance immunotherapy against pancreatic cancer and potentially other KRAS driven malignancies.