1311P - Understanding the basis for intrinsic resistance to KRASG12C inhibitors

Background

Lung cancer is the leading cause of cancer-related deaths worldwide. KRAS is the most frequent mutated oncogen in lung adenocarcinoma (LUAD), but it has been recognized as undruggable for many years. KRASG12C inhibitors (KRASG12Ci), are being tested in clinical trials and have revealed promising results in LUAD patients. With these results, two KRASG12Ci have been approved for the treatment of LUAD patients by the FDA, which marks the first approved targeted therapy for KRAS-mutated tumors. While these therapies hold great promise, they face the same limitation as other targeted therapies, the therapeutic potential of these inhibitors can be impaired by resistance. Deciphering intrinsic resistance mechanisms to KRASG12Ci is of prime relevance to predict which patients may benefit from these therapies and to propose therapeutic alternatives.

Methods

The efficacy of two different KRASG12Ci was tested in different KRASG12C-mutated models, in vitro in a panel of 8 LUAD cell lines and 7 PDX-derived organoids (PDXDO) models and in vivo in a panel of 7 patient-derived xenografts (PDX) models. Thus, we define the intrinsic and resistance models, and compare the genomic (WES) and transcriptomic (WTS) data to find a signature that defines the intrinsic resistance to each drug.

Results

Among the 8 LUAD cell lines, we found 3 very sensitive cell lines and 2 intrinsic resistant ones. Among the 7 PDXDO models, we found 4 sensitive models and 3 intrinsic resistant ones. And among the PDX models we found two very sensitive models and two intrinsic resistant ones. These ratios are representative of what was found among patients in clinical trials. Comparative transcriptomic analysis from sensitive and intrinsic resistant models showed different basal levels of expression and/or activation of downstream signaling pathways of KRAS, ARF or PLC and of various receptors such as ERBB, FGFR or IGF-1R.

Conclusions

1) We found a transcriptomic signature that define the intrinsic resistance, characterized by a greater basal expression and/or activation of some RTKs and signaling pathways. 2) We identificate some molecular alterations which could be responsible of the intrinsic resistance and could acts as predictive biomarkers and/or serve as therapeutic targets in combination with KRASG12Ci.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

L.P.A. was funded by the Comunidad de Madrid, CAM, (B2017/BMD3884), AECC, CRIS, ISCIII (PI17/00778; PI20/00820; AC20/0070) and CIBERONC (CD16/12/00442), and co-funded by FEDER from Regional Development European Funds (European Union). I.F. is funded by i+12 and ISCIII (PI16/01311; PI19/00320; CP21/00052) and co-funded by FEDER from Regional Development European Funds (European Union). A.S. was funded by Ministerio FPU18/06237.

Disclosure

L. Paz-Ares: Financial Interests, Personal, Advisory Board, Speaker fees: Roche, MSD, BMS, AZ, Lilly, PharmaMar, BeiGene, Daiichi, Medscape, Per; Financial Interests, Personal, Advisory Board: Merck Serono, Pfizer, Bayer, Amgen, Janssen, GSK, Novartis, Takeda, Sanofi, Mirati; Financial Interests, Personal, Other, Board member: Genomica, Altum sequencing; Financial Interests, Institutional, Coordinating PI: Daiichi Sankyo, AstraZeneca, Merck Sharp & Dohme Corp, BMS, Janssen-Cilag International NV, Novartis, Roche, Sanofi, Tesaro, Alkermes, Lilly, Takeda, Pfizer, PharmaMar; Financial Interests, Personal, Coordinating PI: Amgen; Financial Interests, Other, Member: AACR, ASCO, ESMO; Financial Interests, Other, Foundation Board Member: AECC; Financial Interests, Other, President.ASEICA( Spanish Association of Cancer Research): ASEICA; Financial Interests, Other, Foundation president: ONCOSUR; Financial Interests, Other, member: Small Lung Cancer Group. All other authors have declared no conflicts of interest.