Figure S2. PI5P4Kα expression enriched in basal compartment.

Characteristics of GEMM cohort used and raw quantification of ATAD2 expression

Additional analyses related to Figure 3.

A large population-based study from Japan reveals both the promise and the limits of genomic profiling in cancer care, and highlights the need for multidimensional data to guide therapy across diverse populations.

Additional analyses of MYC regulation of ATAD2.

TCF7L2 chromatin binding is reduced upon treatment with A947 in CRPC-WNT

Oligonucleotides used in this Study

Supplementary Information 1. Post-workshop survey questions.

Loss-of-function genomic alterations in FANCA occur across multiple cancer types, yet no molecularly tailored therapies have successfully exploited this potential vulnerability. Using complementary unbiased approaches, including a genome-wide CRISPR/Cas9 loss-of-function screen and a high-throughput drug screen in isogenic cancer cell-based models, we identified Aurora kinase A (AURKA) as a reproducible synthetic lethal target of FANCA-deficient cancers. Inhibition of AURKA induced chromosomal instability, micronucleation, and differential mitotic dynamics dependent on FANCA status. Mechanistically, FANCA deficiency is associated with an elevated AURKA expression at both the transcriptomic and protein levels, and with an upregulation of mitotic spindle and G2/M checkpoint gene signatures. Analysis of large-scale cancer genomics datasets, including over 650,000 clinically sequenced tumors, confirms that FANCA is the most frequently altered Fanconi anemia pathway gene across cancers, and that Fanconi anemia-defective tumors exhibit an increased tumor mutational burden and genomic instability. Collectively, our findings point to AURKA inhibition as a promising precision treatment strategy in FANCA-deficient cancers and provide a rationale to further explore this strategy in the clinic.

A947-treatment consistently modulates lineage-defining CRPCWNT signature and master TFs

Figure S1. PIP4K2A expression in human scRNA-Seq dataset.

Supplementary Figure 2. Example case 2.

CRPC-WNT is a clinically relevant subtype that can be targeted by SMARCA2/4 PROTAC degraders

The TCF7L2 promoter interacts with an intragenic enhancer that is kept accessible by the SWI/SNF complex

TCF7L2 regulates pro-proliferative pathways in CRPC-WNT

A947-treatment leads to decreased chromatin accessibility in CRPC-WNT

Figure S6. Prostate morphology resulting from genomic loss of Pip4k2b isoform.

Enhancer of zeste homolog 2 (EZH2) inhibitors have been proposed to counteract lineage plasticity (LP) in prostate cancer and thereby resensitize tumors to androgen receptor (AR) inhibition. In this issue of Cancer Research, Jacobi and colleagues provide new mechanistic insights into EZH2 biology across prostate cancer progression using a genetically engineered mouse model that recapitulates the transition toward a neuroendocrine (NE) phenotype. Unexpectedly, genetic deletion of Ezh2 did not reverse LP but instead promoted the diversification of transcription factor (TF) programs driving NE differentiation. In particular, the loss of EZH2 activated members of the KLF TF family, which contributed to this transcriptional diversification. Moreover, EZH2 deletion altered the chromatin-binding landscape of AR, redirecting it toward KLF-associated genomic sites. Collectively, these results refine our understanding of EZH2 function in prostate cancer: Rather than simply reversing LP, EZH2 loss rewires transcriptional networks and reshapes the AR cistrome. These findings are timely given the growing number of clinical trials testing EZH2 inhibitors in metastatic prostate cancer and highlight the need to define when and how to deploy EZH2 inhibition to exploit its effects on tumor lineage dynamics. See related article by Jacobi et al., p. 889

Supplementary Figure 4. Example case 4.