Abstract 2810: Increasing the efficacy of KRASG12Cinhibitor therapy through the adjuvant use of FAP targeted radiotherapy in a murine model of lung cancer
Authors: Capaccione Kathleen M. , Doubrovin Mikhail , Braumuller Brian , Huang Sophia , Bhatt Nikunj , Momen-Heravi Fatemeh , Molotkov Andrei , Kissner Michael , Ali Alessandra , Mintz Akiva 
Published: April 2023

Abstract
The purpose of this study was to evaluate the combined effects of KRAS targeted therapy and FAP targeted radiotherapy compared to either therapy alone in an animal model of lung cancer. KRAS is a protein that acts as a molecular switch regulating cell proliferation mediated through binding of GTP versus GDP. When mutated, the switch remains “on” and cells undergo unrestrained proliferation. KRAS mutations are frequently found in lung cancer and it appeared for years as if they could not be inhibited. Recently KRASG12C inhibitors have been developed by targeting a site adjacent to the binding pocket that induces a conformational change in the protein preventing GTP binding thus inhibiting unrestrained cell cycling. While a promising advance, KRAS targeted therapy does not confer a durable response and therefore it is essential to develop adjuvant therapies that enhance efficacy of KRAS targeting agents. FAP targeted radiotherapy is a new anticancer therapeutic that delivers a radioactive payload directly to tumors and has been shown to increase efficacy when used with immunomodulatory therapy. We studied the effect of KRAS targeted therapy alone and in combination with FAP targeted radiotherapy. Animals were implanted with KRASG12C heterozygote LLC1 lung cancer cells and treated according to the following groups: untreated control, sotorasib treatment, 177Lu-FAPI-04 treatment, and combined treatment. Tumor growth was evaluated every 2-3 days and animals were euthanized at 21 days and tumors extracted for analysis. anti-Ki67 and anti-caspase-3 immunofluorescence assessed cell cycling and apoptotic cell death, respectively. Immunoassays were performed to quantify soluble analytes, including IL-12p70, TNF-α, TGF-β1, and IFN-γ. Tumor growth in dual treated animals was significantly reduced compared to either therapy alone. Ki67 immunofluorescence demonstrated a significantly decreased number of cells in the combined therapy group than either therapy alone (p=0.01 and 0.02 when compared to sotorasib alone and radiotherapy alone, respectively). Anti-caspase-3 immunofluorescence demonstrated a significant increase in positive cells in the combined group compared to animals treated with sotorasib alone (p=0.003). Immunoassays assessing expression of TNF-α, TGF-β1, and IFN-γ from tumors from animals in each treatment group demonstrated statistically significant differences (p=0.006, p=0.03, p=0.02, respectively). Combined KRAS targeted therapy and FAP targeted radiotherapy results in decreased tumor growth compared to either therapy alone. Effects are mediated through decreased cell cycling, increased apoptotic cell death, and changes in key cell signaling pathways. Future translational studies will assess this therapy combination in patients to evaluate its ability to increase response to therapy.
Citation Format: Kathleen M. Capaccione, Mikhail Doubrovin, Brian Braumuller, Sophia Huang, Nikunj Bhatt, Fatemeh Momen-Heravi, Andrei Molotkov, Michael Kissner, Alessandra Ali, Akiva Mintz. Increasing the efficacy of KRASG12Cinhibitor therapy through the adjuvant use of FAP targeted radiotherapy in a murine model of lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2810.