High chemopreventive and therapeutic efficacy of Id1 inhibition in KRAS-mutant (KM) adenocarcinoma (AD) non-small cell lung cancer (NSCLC)

Background: Id1 is an independent prognostic factor in NSCLC-AD. Id1 silencing impairs cell viability and migration of NSCLC-AD cell lines. KRAS is the most frequently mutant gene in NSCLC with no specific therapies clinically available. Here we evaluate Id1 as a potential chemopreventive and therapeutic target in a humanized mouse model of KM NSCLC-AD. Methods: Several human lung AD cell lines with known mutations (H1792-604, H2009, H358, H1568, H1437, H1703 and H2126) were selected for Id1 silencing using inducible short hairpin RNA (shRNA). Humanized AD xenograft mouse models were generated by subcutaneous injection of H1792-604 and H2009 cell lines (Id1 silenced or Id1 wild type) in flanks of immunodeficient mice. Id1 silencing was activated at the time of tumor cell inoculation (chemoprevention assay) or once the tumors were established (therapeutic assay). Results: Id1 inhibition was achieved in all selected cell lines compared to their controls. In vivo, in the chemoprevention assay we observed a significant decrease in tumor volume in mice injected with Id1 silenced H1792-604 cells (60% ± 32.39) compared to the control group (356.29% ± 115.32) (p < 0.001). Moreover, mice injected with Id1 silenced H2009 cells never developed tumors compared to control mice (168.35 ± 68.71) (p < 0.001). In the therapeutic assay, the activation of inducible silencing of Id1 in established tumors induced a significant reduction of tumor volume in both xenograft models. Id1 inhibition induced a partial response in 40% of the tumors after injection of H1792-604 cells and in 100% of tumors in H2009 inoculated mice. Conclusions: These findings encourage further evaluation of Id1 as a potential therapeutic target in KM NSCLC-AD patients. Legal entity responsible for the study: Clínica Universidad de Navarra Funding: Clínica Universidad de Navarra Disclosure: All authors have declared no conflicts of interest.