Researchers have made a major breakthrough in understanding how advanced prostate cancer develops resistance to poly(ADP-ribose) polymerase inhibitors (PARPi), a critical class of drugs for treating metastatic castration-resistant prostate cancer (mCRPC). A study published in Cancer Cell reveals the genetic adaptations tumors use to evade these therapies, offering insights that could lead to more effective treatments.
PARPi has revolutionized the treatment of mCRPC, particularly in patients with defects in DNA repair genes like BRCA2 and PALB2. However, resistance frequently develops, diminishing the long-term effectiveness of these therapies. By analyzing circulating tumor DNA (ctDNA) from patients, researchers identified key genetic changes that enable tumors to survive PARP inhibition.
One of the most striking findings was the prevalence of reversion mutations in BRCA2 and PALB2-mutated tumors. These mutations restore the function of previously defective DNA repair genes, allowing cancer cells to repair the DNA damage that PARPi aims to exploit. The study revealed that nearly 80% of tumors with BRCA2 or PALB2 mutations developed these reversion mutations during treatment, which was closely tied to shorter progression-free and overall survival.
The researchers also identified a critical role for microhomology-mediated DNA repair, a pathway driven by the enzyme DNA polymerase theta (POLQ). This mechanism not only facilitates reversion mutations but also presents a potential therapeutic target. By combining PARPi with POLQ inhibitors, researchers hope to block this pathway and prevent resistance from emerging.
In tumors with complete BRCA2 deletions, which cannot undergo reversion mutations, resistance arose through the selection of rare subclones retaining partial BRCA2 functionality. These subclones became dominant as the disease progressed, highlighting another pathway through which cancer cells evade treatment.
“Overall, our study highlights the complexity of the evolution of resistance to PARPi therapy in prostate cancer and emphasizes the opportunity of ctDNA to improve patient outcomes by enabling the precise and real-time monitoring of patients,” the authors concluded.
This research underscores the need for combination therapies to counteract the multiple mechanisms of resistance in advanced prostate cancer. Strategies such as pairing PARPi with POLQ inhibitors or targeting specific subclones could extend the effectiveness of these drugs and improve patient outcomes.
The findings represent a critical step forward in the fight against one of the most challenging forms of cancer. By unraveling the genetic underpinnings of drug resistance, researchers are paving the way for next-generation treatments that offer new hope for patients with advanced prostate cancer.
