2233MO - CDC7 inhibition constrains lineage plasticity and prevents resistance and neuroendocrine transformation in the lung and prostate

Background

In lung and prostate adenocarcinomas (ADs), neuroendocrine (NE) transformation to small cell carcinoma (SCC) occurs on targeted therapy in up to 14% and 30% of EGFR-mutant lung and AR-dependent prostate tumors, respectively. SCCs, occurring de novo or after NE transformation, lead to poor prognosis due to the sparse and ineffective treatment options available, based on classic chemotherapy. Thus, the identification of therapeutic targets to (1) prevent NE transformation and (2) to efficiently treat SCCs are unmet clinical needs.

Methods

We performed CRISPR screens to identify therapeutic targets for SCC, which were validated genetically and pharmacologically in vitro and in vivo in lung and prostate adeno-to-NE transformation models and SCC patient-derived xenografts (PDXs), as well as in isogenic cell lines.

Results

Our screen nominated CDC7, involved in DNA replication, as a therapeutic vulnerability in SCC. Simurosertib, a CDC7 inhibitor in phase II trials, dramatically sensitized an array of chemotherapy-naïve and -resistant SCC PDXs to chemotherapeutic agents used in the first- and second-line settings for these tumors, respectively, without toxicity issues at the concentrations used. Also, we observed CDC7 upregulation in NE-transforming clinical specimens, occurring already in pre-transformation ADs. Consistently, we observed increased CDC7 expression in the lung and prostate AD population at high risk of NE transformation (TP53/RB1-mutated), and that double TP53/RB1 knock out induces not only high CDC7 expression in lung and prostate AD cell lines, but also increased sensitivity to simurosertib. Importantly, simurosertib was able to suppress the acquisition of a NE phenotype and dramatically delay tumor relapse in an array of lung and prostate patient-derived models of NE transformation treated with targeted therapy.

Conclusions

CDC7 inhibition prevents NE transformation in lung and prostate AD, and exquisitely sensitizes NE-transformed or de novo SCCs to chemotherapy. The availability of CDC7 inhibitors currently under clinical testing will allow immediate translation of these results in two settings with extremely limited and rather ineffective therapeutic options available.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

This study was supported by PO1 NIH PO1CA163227 (Prostate Cancer Donor Program), NIH T32 CA1600001 (AQV), K08 CA-248723 (AC), R01CA264078 (CMR), The Doris Duke Foundation (Grant 2021184) (MCH), P50CA97186 (MCH), R35 CA263816 (CMR), U24 CA213274 (CMR), P30 CA008748, and by the Druckenmiller Center for Lung Cancer Research (AQV, CMR).

Disclosure

î Quintanal-Villalonga: Financial Interests, Invited Speaker: AstraZeneca; Financial Interests, Research Grant: Jazz, Duality, Foghorn. C.M. Rudin: Financial Interests, Advisory Board: AbbVie, Amgen, Ascentage, AstraZeneca, Bicyle, Celgene, Daichi Sanko, Genentech-Roche, Ipsen, Jazz, Lilly, Pfizer, PharmaMar, Syros, Vavotek, Bridge Medicines, Earli, Harpoon. All other authors have declared no conflicts of interest.