TRAIL inducing drug, ONC201 prevents adenocarcinoma in transgenic KRAS G12V mouse lung cancer model

Lung cancer is one of the leading cancers worldwide. Around 226,000 people will be diagnosed with lung cancer in the US during 2025. Almost one-fourth of all lung cancers are KRAS-mutated tumors, which are very challenging to treat and have poor prognosis. Interception of lung cancer is of utmost importance to reduce the burden and mortality. However, there are currently no interception agents approved by FDA. TCGA database revealed that the apoptosis mediating TRAIL expression is lost during the progression of lung tumor stages. ONC201 (Dordaviprone) is an orally active TRAIL inducing small molecule compound with proven preclinical efficacy and is being clinically evaluated against multiple cancers. Previously we reported the cancer prevention potential of ONC201 in an NNK-induced lung cancer model in A/J mice. Here, we evaluated the efficacy of ONC201 in an aggressive KRAS G12V lung tumor mouse model. Male and female KRAS G12V mice were generated by inhouse breeding. Six-week aged mice were randomized (n=20/sex) into placebo and interception groups. Beginning at 8 weeks of age (early adenoma stage) mice were gavaged one of the doses of ONC201 (0, 25, 50, 100mg/kg in PBS vehicle) twice weekly for 28 weeks. All mice were euthanized at 36 weeks of age, and lungs were evaluated to determine tumor incidence and multiplicity. Both the male and female KRAS G12V mice in placebo group developed lung tumors (~100% incidence) with average tumor multiplicity of 12.2±1.5 (male) and 11.7±0.8 (female) per mouse. ONC201 treatment resulted in significant reduction in total lung tumors multiplicity in both male (34%-63% less; p<0.05-p<0.0001) and female (33%-55% less; p<0.001-p<0.0001) mice in a dose dependent-manner as compared to their control group. H&E stained lung tumor sections were histologically classified as adenomas (AD), and adenocarcinomas (ADCA). Placebo mice showed multiplicity of 9.3±1.3 ADCA, and 12±1.2 AD+ADCA in male; 8.3±0.6 ADCA, and 11.61±0.87 AD+ADCA in female mice. Histopathology results indicated dose-dependent reduction in ADCA multiplicity in ONC201 treated mice in male (53%-86%; p<0.001 - p<0.0001) and female mice (54%-79%; p<0.0001) when compared to their respective control mice. There was no clinical sign of toxicities observed in all three doses tested in both male and female mice. Immunoblotting and IHC results revealed that TRAIL inducing ONC201 triggering the downstream signaling molecules (TRAIL, DR5, FADD, Apaf1), elevated apoptosis markers (Caspases), concurrently reduces the proliferation markers (PCNA, Cyclin D1, EGFR, Ki67). In conclusion, ONC201 demonstrated strong efficacy in preventing lung cancer in two preclinical mouse models and warrants further clinical development for the prevention of lung tumor in high risk populations. (Project funded 100% with Federal funds from NCI, NIH, DHHS, under Contract 75N91019D00020_75N91022F00003)