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
1741P - Ethically-sensitive clinical scenarios in adult patients with sarcomas: A real-world single-institution survey and a classification attempt
Presenter: Paolo G. Casali
Session: Poster session 06
1742P - Factors influencing awareness of patient associations in sarcoma: A multicentric cross-sectional study
Presenter: Pau Mascaró Baselga
Session: Poster session 06
1743P - A phase II study of fruquintinib in the 1L or 2L treatment of unresectable metastatic soft tissue sarcoma
Presenter: Zhiguo Luo
Session: Poster session 06
1745P - How to optimize the response with trabectedin in soft tissue sarcomas? Data from a high-volume center
Presenter: Sebastian Diaz
Session: Poster session 06
1746P - Real-world characterization of patients with advanced or metastatic dedifferentiated liposarcoma (DDLPS) in Japan in MASTER KEY project
Presenter: Kenji Tsuchihashi
Session: Poster session 06
1747P - Changes in global health status (GHS) in patients with advanced soft tissue sarcoma (STS) treated with first line palliative chemotherapy: Primary outcomes from the HOLISTIC study
Presenter: Evelyne Roets
Session: Poster session 06
1748P - A prospective, phase II study of tislelizumab administered in combination with eribulin and anlotinib for patients (pts) with advanced adult oft tissue sarcoma (TEASTS)
Presenter: Xi Guo
Session: Poster session 06
1749P - Vertebral MRI in the screening for bone metastasis in myxoid liposarcoma: Is it justified?
Presenter: Tania Moussa
Session: Poster session 06
1750P - Incidence of cardiotoxicity after high cumulative dose of anthracyclines in adult patients with advanced soft tissue sarcomas: A systematic review and meta-analysis
Presenter: Gale Rizzae Mercado Alcala
Session: Poster session 06
1751P - Clinical and survival data of 336 myxoid liposarcoma patients: The Gustave Roussy experience
Presenter: Tarek Assi
Session: Poster session 06