Assistant Professor Cleveland Clinic Foundation Cleveland, OH, United States
Background: Despite major strides in therapy, including combinations of immunotherapy with tyrosine kinase inhibitors, metastatic/advanced cases of clear cell Renal Cell Carcinoma (ccRCC) present a clinical challenge. Consequently, the need for novel targets that complement existing therapies remains urgent. Recently, interrogating genetic dependencies that were enriched in the kidney lineage cancer cells, we identified BCL2L1, which encodes the BCL-XL anti-apoptotic protein, as a prominent druggable vulnerability in ccRCC. Here, we describe our ongoing studies to establish the mechanisms underlying BCL-XL dependency and establish strategies to clinically exploit this dependency in ccRCC.
Results: In previous work, we showed that a subset (~40%) of ccRCCs were highly sensitive to both genetic and pharmacologic inactivation of BCL-XL. Interestingly, neither expression of the BCL family proteins nor p53 mutational status was sufficient to predict dependence on BCL-XL. Instead, by relying on transcriptomics analysis and functional perturbation studies, we found that a mesenchymal cell state was both necessary and sufficient to confer BCL-XL dependence. Using gene-expression studies, we have begun addressing the biological basis of this cell state driven dependency. Additionally, we find that BCL-XL inhibition can augment therapeutically-relevant strategies to manage ccRCC, including NK-cell mediated killing and mTOR inhibition. Finally, using CRISPR/Cas9 screens we find genetic strategies to promote sensitivity to BCL-XL inhibitors in otherwise insensitive ccRCC cancers.
Conclusions: Targeting BCL2 family proteins has recently generated renewed interest due to the development of novel inhibitors with improved selectivities and reduced toxicities. Our timely studies utilized genetic dependency maps to highlight the hyperdependency of mesenchymal ccRCCs on BCL-XL. We find that BCL-XL represents a targetable dependency in ~30-40% human tumors; but its blockade, additionally, augments response to other therapies. Altogether, we report the utility of apoptosis modulators against aggressive ccRCCs.
