Osalmid sensitizes clear cell renal cell carcinoma to navitoclax through a STAT3/BCL-XL pathway

Area of Science:

• Oncology
• Cancer Biology
• Drug Discovery

Background:

• Clear cell renal cell carcinoma (ccRCC) is a deadly cancer with poor treatment outcomes due to apoptosis resistance.
• Inducing tumor cell senescence followed by senolytics is a potential cancer therapy strategy.
• The efficacy of this strategy in ccRCC remains largely unexplored.

Purpose of the Study:

• To identify targetable genes for ccRCC treatment.
• To evaluate a novel therapeutic approach combining osalmid and navitoclax for ccRCC.
• To elucidate the underlying mechanism of this combination therapy.

Main Methods:

• Utilized the Dependency Map (DepMap) portal for whole-genome CRISPR screening to identify essential genes in ccRCC.
• Tested the combination of osalmid (RRM2 inhibitor) and navitoclax (BCL-XL inhibitor) in various ccRCC preclinical models.
• Investigated the mechanistic pathways including dNTP generation, senescence induction, STAT3 activation, and BCL-XL/BCL-2 family protein expression.

Main Results:

• Ribonucleotide reductase subunit 2 (RRM2) was identified as a critical targetable gene in ccRCC.
• The combination of osalmid and navitoclax demonstrated efficacy across diverse ccRCC cell lines, xenografts (CDX, PDX), and organoids (PDO).
• Osamild induced ccRCC cell senescence by inhibiting dNTP synthesis, leading to STAT3 activation and increased BCL-XL, sensitizing cells to navitoclax.

Conclusions:

• The combination of osalmid and navitoclax represents a novel and effective therapeutic strategy for ccRCC.
• Targeting RRM2 with osalmid to induce senescence and subsequent BCL-XL upregulation creates a vulnerability exploitable by navitoclax.
• This approach holds significant potential for improving ccRCC patient outcomes.