2211MO - Uncovering the mechanisms of persistent disease in RET-altered thyroid cancers: Insights from patient-derived xenograft models treated with selective RET inhibitors

Background

Selective RET inhibitors have showed promising activity in advanced thyroid cancers harbouring RET mutations or fusions. Initial heterogenous mechanisms of resistance at time of disease progression have been described. However, little is known about the mechanisms of persistent disease at the time of maximum response and the pathways activated at regrowth.

Methods

We generated patient-derived xenograft (PDX) models from two patients with advanced thyroid cancers: one from a papillary thyroid tumor with a NCOA4-RET fusion and one from a medullary thyroid carcinoma with a RETM918T mutation. In both cases, RET/MAPK pathway was constitutively activated conferring a hyperproliferative phenotype. We treated both mouse models with multikinase inhibitors (MKI) (cabozantinib, lenvatinib and axitinib) or with a selective RET inhibitor (BLU667). RNAseq analyses were performed in control vehicle-treated tumors and xenografts treated short (5 or 20 days) or long time exposure (20 or 170 days) with BLU667 and after treatment release.

Results

Both PDX models responded to MKI and BLU667 with significant deeper responses with BLU667. The RET-fused PDX showed a more acute and prolonged response to BLU667 than the RETM918T model. Only with selective RET inhibitor we observed a profound effect on the whole gene expression profile of human and mouse cells in all analysed xenograft tumors. Longer treatments revealed a distinctive profile resembling a residual disease. Proliferation genes were downregulated upon treatment, whereas antigen presentation, chemokines and immune response gene sets were positively enriched in both PDX models. Interestingly, such immune reaction to RET/MAPK pathway repression was sustained upon BLU667 treatment release. Such immune reaction affected the gene expression of both cancer (human) and stroma (mouse) cells.

Conclusions

These results pave the way for a rational combination of RET inhibitors and immunotherapy in the two scenarios, as primary therapy to reduce the minimal residual disease and at time of resistance to selective RET inhibition.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Instituto de Salud Carlos III (ISCIII).

Disclosure

A. Garcia Alvarez: Financial Interests, Personal, Advisory Board: ADACAP (Novartis); Other, Expenses (Travel, Congress inscription): Advanz, Eisai, Ipsen, ADACAP (Novartis). J. Hernando: Financial Interests, Personal, Advisory Board: Eisai, Ipsen, Novartis, AAA, Angelini, Pfizer, Roche. A. Vivancos: Financial Interests, Personal, Advisory Board: Roche, Bristol Myers Squibb, Guardant Health, Bayer, Incyte; Financial Interests, Personal, Stocks/Shares: Reveal Genomics; Financial Interests, Institutional, Research Grant, Preclinical Research Grant: Bristol Myers Squibb, Roche, Incyte. J. Capdevila Castillon: Financial Interests, Personal, Invited Speaker: Novartis, Novartis, Pfizer, Ipsen, Exelis, Bayer, Eisai, Advanced Accelerator Applications, Amgen, Sanofi, Lilly, Merck Serono; Financial Interests, Personal, Advisory Board: Pfizer, Ipsen, Exelis, Bayer, Eisai, Advanced Accelerator Applications, Amgen, Sanofi, Lilly, Merck Serono, Esteve, ITM; Financial Interests, Personal, Research Grant: Novartis, Pfizer, AstraZeneca, Advanced Accelerator Applications, Eisai, Bayer. All other authors have declared no conflicts of interest.