Abstract 1385P
Background
Despite improvements in therapy, lung adenocarcinoma (LUAD) mortality remains high, with fewer than 20% of patients surviving after 5 years. Therefore, overcoming resistance to the already existing therapies and identifying new strategies remains a high priority. Approximately 20% of Kirsten rat sarcoma viral oncogene homolog (KRAS) mutant LUAD carry loss-of-function (LOF) KEAP1 mutations, which confer the worst prognosis of all LUAD subtypes as patients do not respond to standard of care, radiation, immunotherapy, chemotherapy or covalent KRASG12C inhibitors.
Methods
Here, we used two (2D) and three-dimensions (3D) in vitro cultures and in vivo pre-clinical models to uncover resistance mechanisms and also vulnerabilities of KEAP1-mutant LUAD.
Results
We found that, although Keap1 loss did not lead to growth differences in 2D cultures, in 3D its loss led to increased spheroids’ size (p<0.001) and higher EdU staining. Importantly, similar patterns were seen with the pharmacological inhibition of Keap1 by KI696 and rescued by the knockout of NRF2. In addition, we observed an increased expression of NRF2 targets, NQO1 (p<0.01) and HO1 (p<0.001), in Keap1-knockout spheroids compared to those cultured in two-dimensions, suggesting a greater requirement of NRF2 pathway in the 3D system. We also explored how Keap1-mutated tumors respond to KRAS inhibitors (KrasG12Di). Keap1-low/NRF2-high tumors were significantly less sensitive to the newly developed KrasG12D inhibitor, MRTX1133 (Mirati Therapeutics), measured by both tumor size (p<0.05) and tumor weight at end point (p=0.01). RNAseq of lung spheroids treated with MRTX1133 are being performed to bring to light how the loss of Keap1 is able to support survival upon the treatment with KrasG12D inhibitors.
Conclusions
Taken together these findings will contribute to the understanding of resistance mechanisms and will give us insights of therapeutic strategies to determine the best-individualized treatments.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
Fernando Simabuco and Thales Papagiannakopoulos.
Funding
The São Paulo Research Foundation.
Disclosure
All authors have declared no conflicts of interest.
Resources from the same session
1731P - Phase II study of the CDK2/4/6 inhibitor TQB3616 capsules in patients with dedifferentiated liposarcomas (DDLPS)
Presenter: Jing Chen
Session: Poster session 06
1732P - Primary pulmonary sarcoma: A EURACAN project
Presenter: Stephane Collaud
Session: Poster session 06
1733P - Update on gallant: A phase II study using metronomic gemcitabine, doxorubicin and docetaxel plus nivolumab in previously treated sarcoma
Presenter: Neal Chawla
Session: Poster session 06
1734P - Evaluation of nivolumab in cutaneous angiosarcoma management: The ANGIOCHECK study
Presenter: Yasuhiro Fujisawa
Session: Poster session 06
1735P - Sintilimab plus anlotinib in patients with advanced sarcomas (SINANLOSARC): A single-centre, single-arm, phase II trial
Presenter: Zengjun Liu
Session: Poster session 06
Resources:
Abstract
1736P - An open label phase IIa study evaluating the preliminary efficacy of intratumoural tigilanol tiglate (TT) in advanced and/or metastatic soft tissue sarcoma (STS)
Presenter: Edmund Bartlett
Session: Poster session 06
1737P - A comparison of the risk prediction models sarculator and PERSARC in patients with localized soft tissue sarcoma of the extremities and trunk wall
Presenter: Marthe Kobbeltvedt
Session: Poster session 06
1738P - Results from the conference on challenges in sarcoma (CCS) 2024
Presenter: Christian Rothermundt
Session: Poster session 06
1739P - Linnovate: A phase I/II study of safety/efficacy using lurbinectedin combined with ipilimumab and nivolumab for advanced soft tissue sarcoma (NCT05876715) - Interim analysis of phase I part
Presenter: Erlinda Gordon
Session: Poster session 06
1740P - Surufatinib combined with gemcitabine in soft tissue sarcoma (STS) patients failed with anthracyclines chemotherapy or monotherapy post-anlotinib progression: A multi-center, phase II trial
Presenter: Yuhong Zhou
Session: Poster session 06