Abstract 228P
Background
Even if the development of targeted therapies in lung adenocarcinomas (LUADs) has improved outcomes in patient subsets, intra-driver genetic heterogeneity underlies the diversity of patient responses to such therapies, dramatically impacting patient survival. Co-occurring alterations in the genes SMARCA4, STK11, and KEAP1 predict exceptionally poor prognosis in patients with LUAD.
Methods
Here, we characterize the effects of SMARCA4 loss in the context of STK11/KEAP1-mutated LUADs by performing multi-omic analyses on clinical specimens and isogenic preclinical models, followed by functional validation in vitro and in vivo.
Results
Clinical analyses of the MSK-LUAD cohort (N=5049) confirmed strikingly poorer outcomes and increased metastasis in patients with SSK tumors. Transcriptomic profiling in a subset of tumors from this cohort (N=49) revealed upregulation of genes involved in epithelial-to-mesenchymal transition (EMT) and metastasis, as well as in TGFβ signaling, specifically in SSK tumors. To further interrogate these differences, we engineered isogenic LUAD cell line models with SMARCA4-knock out (KO), SK double KO, and SSK triple KO. Multi-omic characterization of these revealed upregulation in metastasis- and stemness-related pathways in the SSK-KO models, as well as in the TGFβ signaling pathway, consistent with our clinical transcriptomic data. In line with these results, functional studies revealed increased EMT marker expression, migration/invasion and colony formation abilities in the SSK models in vitro, which were reverted by treatment with the TGFβ inhibitor SB-431542. Remarkably, pharmacological inhibition of TGFβ signaling sensitized SSK cells to different therapies used in the treatment of LUAD, such as the KRAS inhibitor sotorasib and cisplatin.
Conclusions
SMARCA4 inactivation upregulates TGFβ signaling in LUAD tumors with inactivated STK11/KEAP1, inducing an aggressive phenotype. Pharmacological inhibition does not only suppress this phenotype, but also sensitizes to cytotoxic or targeted therapy. These results provide mechanistic insight into the aggressiveness of SSK-mutant LUADs and nominates TGFβ signaling as a therapeutic vulnerability in these.
Legal entity responsible for the study
The authors.
Funding
This study was supported by PO1 NIH PO1CA163227 (Prostate Cancer Donor Program), NIH T32 CA1600001 (to AQV), K08 CA-248723 (to AC), R01CA264078 (to CMR and, HAY), The Doris DukeFoundation (Grant 2021184) (to MCH), P50CA97186 (to MH and, CM), R35 CA263816 (to CMR), U24 CA213274 (to CMR), P30 CA008748, Yasuda Medical Foundation (to KK), and by the American Lung Association (to AQV), by Druckenmiller Center for Lung Cancer Research (to AQV, KK and, CMR) and by the Howard Hughes Medical Institute (to CLS).
Disclosure
Quintanal-Villalonga: Financial Interests, Personal, Invited Speaker: AstraZeneca; Financial Interests, Personal, Research Grant: Jazz, Duality, Foghorn. C.M. Rudin: Financial Interests, Personal, Advisory Role: AbbVie, Amgen, AstraZeneca, D2G, Daiichi Sankyo, Epizyme, Genentech/Roche, Ipsen, Jazz, Kowa, Lilly, Merck, Auron, Bridge Medicines; Financial Interests, Personal, Affiliate: Syros; Financial Interests, Personal, Advisory Board: Disco, Earli, Harpoon. All other authors have declared no conflicts of interest.