Antagonizing CD105 enhances radiation sensitivity in prostate cancer

Area of Science:

• Oncology
• Radiation Oncology
• Molecular Biology

Background:

• Radiation resistance affects 30-50% of prostate cancer patients, hindering treatment efficacy.
• Understanding radiation resistance mechanisms is crucial for developing novel therapeutic strategies.
• CD105 signaling is implicated in radioresistance downstream of BMP and TGF-β pathways.

Purpose of the Study:

• To investigate the role of CD105 in radiation resistance in prostate cancer.
• To evaluate the efficacy of TRC105, a CD105-targeting antibody, in combination with irradiation.
• To elucidate the molecular mechanisms underlying CD105-mediated radio-sensitization.

Main Methods:

• Utilized cell culture and xenograft models of prostate cancer.
• Investigated the effects of TRC105 and irradiation on clonogenicity, DNA damage repair, and cell cycle progression.
• Analyzed the involvement of CD105, BMP signaling, SIRT1, p53, and PGC-1α in radiation response.
• Assessed ATP levels and metabolic pathways in response to treatment.

Main Results:

• Combining TRC105 with irradiation significantly reduced prostate cancer cell clonogenicity.
• Radiation-induced CD105/BMP signaling upregulates SIRT1, stabilizing p53 and activating PGC-1α.
• TRC105 and irradiation combination delayed DNA repair and depleted ATP stores, causing G2 cell cycle arrest.
• Tumor growth was significantly reduced in xenograft models when TRC105 was combined with irradiation (p=10⁻⁹).

Conclusions:

• CD105 mediates a radiation-resistance pathway involving SIRT1, p53, and PGC-1α, impacting DNA repair and cellular metabolism.
• Targeting the CD105-SIRT1 axis represents a novel synthetic lethality strategy to overcome radiation resistance in p53-functional prostate cancers.
• Combining TRC105 with radiation offers a promising approach to enhance treatment outcomes for prostate cancer patients with radiation-resistant disease.