Renal medullary carcinomas depend upon SMARCB1 loss and are sensitive to proteasome inhibition

Area of Science:

• Oncology
• Genetics
• Molecular Biology

Background:

• Renal medullary carcinoma (RMC) is a rare and aggressive kidney cancer predominantly affecting individuals of African descent with sickle cell trait.
• The genetic underpinnings of RMC have been poorly understood, hindering therapeutic development.

Purpose of the Study:

• To elucidate the molecular mechanisms driving RMC pathogenesis.
• To identify novel therapeutic vulnerabilities in SMARCB1-deficient cancers.

Main Methods:

• Development of patient-derived RMC models.
• Whole-genome sequencing to identify genetic alterations.
• RNAi and CRISPR-Cas9 loss-of-function genetic screens.
• Small-molecule screening.
• Biochemical and functional assays.

Main Results:

• Identified loss-of-function fusion events in one SMARCB1 allele with concurrent loss of the other allele as critical for RMC survival.
• Discovered that the ubiquitin-proteasome system (UPS) is essential for RMC cell viability.
• Demonstrated that UPS inhibition leads to G2/M cell cycle arrest due to cyclin B1 accumulation.
• Confirmed these findings in other cancers with SMARCB1 loss, highlighting the role of UBE2C.

Conclusions:

• Loss of SMARCB1 creates a synthetic lethal dependency on the ubiquitin-proteasome system in RMC and other related cancers.
• This dependency provides a strong rationale for targeting the UPS with proteasome inhibitors in clinical trials for SMARCB1-deficient malignancies.