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P123. Patient-Derived Lung Tumor Organoids as a Platform to Assess Novel Multi-Targeted Kinase Inhibitors

Saturday, March 7, 2026
9:49 AM - 9:56 AM MST
Location: 101A-C
Introduction: Despite advances in targeted therapies, single-agent approaches and their combinations have shown limited efficacy in relapsed/refractory lung cancer. To overcome this, we developed novel multi-kinase inhibitors (MKIs) via in silico design that target multiple tumor-promoting pathways. LCI133 inhibits AURKA/B, CDK4/6, and CDK9, while LCI139 targets AURKA/B, PI3K, CDK4/6, and CDK9 kinases that regulate mitogenic signaling, cell cycle progression, and transcription. This study evaluates their efficacy in patient-derived lung tumor organoids.


Methods:

Lung cancer specimens were collected under an approved IRB protocol. PTOs were created from unsorted tumor cell suspensions cultured in PEPGEL matrix (n = 7 patients). Organoids were treated with LCI133, LCI139, single-agent inhibitors - Alisertib (AURKAi), Barasertib (AURKBi), Buparlisib (PI3Ki), Ribociclib (CDK4/6i), and AZD4573 (CDK9i) for 72 hours at 37oC. Cell viability was assessed using Promega 3DATP reagent and apoptosis by Annexin V binding and caspase-3/7 and caspase-8 activity assays. Target engagement and pathway modulation were assessed by immunoblotting for phospho-Akt, phospho-Rb, phospho-RNA polymerase II, MCL-1, and p53. Statistical analyses were done via Student T test and One Way Anowa, with p< 0.05 considered significant.

 


Results:

LCI 133 reduced PTO viability by 51.4% at 1 μM (p< 0012), while lower concentrations (0.25 and 0.5 μM) showed no significant effect. In contrast, LCI 139 had superior dose-dependent efficacy: 49% reduction  at 0.25 μM ( (p< 0.0018), 62% at 0.5 μM, and 78.4% at 1 μM (p< 0.0001). Comparing LCI139 (1 μM) to equimolar concentrations of single-agent inhibitors after 72 hours of treatment showed that LCI139 reduced by 80% p< 0.0001 compared to single agents: 34% (AURKAi) p< 0.0001, 24% (AURKBi) p< 0.0001, 29% (PI3Ki) p< 0.0001, 6.9% (CDK4/6i) p< 0.43, and 50.9% (CDK9i) p< 0.0001. Both LCI 133 and LCI 139 (1 μM) significantly increased caspase-3/7 (LCI 139 p< 0.0001, LCI 133 p< 0.05) and caspase-8 activity , indicating caspase-dependent apoptosis. Annexin V staining confirmed apoptosis in treated PTOs. Immunoblotting showed decreased pAkt and pRb expression and reduced p-RNA polymerase II, MCL-1, and p53, suggesting cell cycle arrest causing apoptosis.

 


Conclusions:

LCI133 and LCI139 demonstrate potent anti-tumor activity in patient-derived lung cancer organoids, with LCI139 showing superior dose-dependent efficacy and outperforming single-agent kinase inhibitors. These findings support further preclinical development and evaluation of MKIs for relapsed and refractory lung cancer.

Learning Objectives:

  • Participants should be able to identify the advantages of using multi-targeted kinase inhibitors over single-agent therapies in refractory/relapsed lung cancer.
  • Participants should be able to recognize the rationale of using patient-derived lung tumor organoids to test the potency and efficacy of multi-targeted kinase inhibitors.