Therapeutic validation of single‐ and double‐anti‐MYC and anti‐kRAS approaches for the treatment of Ovarian Cancer
Authors: DeSouza Harriet E. , Brooks Tracy A. 
Published: June 2021

Ovarian cancer is the fifth leading cause of cancer death in women, with the highest mortality rate of any cancers of the female reproductive system. If caught while still locally contained, 5‐year survival rates are >85%, but regional or distant metastatic disease is associated with a survival rate of <40%. More aggressive disease is associated with the amplification of key oncogenes, notably MYC and kRAS. MYC has both transcriptional and non‐transcriptionally‐related functions that mediate cell proliferation, chemotherapeutic resistance, flexible (Warburg) metabolism, and angiogenesis. kRAS is a GTPase that mediates communication between extracellular receptors for growth factors, such as EGFR, and intracellular growth responses through the Raf/Mek/Erk pathway. Each oncogene has been validated as a potential target in select ovarian cancer cell lines as a means to either directly mediate cell death, or to enhance chemotherapeutic efficacy. We examined the effects of knocking down either MYC, kRAS, or the combination of both in ovarian cancer cells with amplified MYC (CaOv‐3) or kRAS (SKOV‐3, OV56) that vary in their inherent responsiveness to cisplatin, paclitaxel (OV56 > CaOv‐3 > SKOV‐3), and doxorubicin (SKOV‐3 > CaOv‐3 > OV56). The effects of MYC and/or kRAS knockdown in these cells and with these chemotherapeutic agents has not previously been examined. Cellular effects after oncogene knockdown were examined by morphology and cell viability, and in combination with chemotherapeutic agents. As expected, knocking down MYC in CaOv‐3 cells demonstrated a notable morphological effect, as well as a significant decrease in cellular growth. Knocking down kRAS had a modest effect on the growth of these cells and the combination of knocking them both down was additive. Only the combination, however, demonstrated significant enhancement of cisplatin‐induced cell death. OV56 cells were more sensitive to targeted kRAS knockdown, as compared to SKOV‐3 cells, and were only moderately responsive to anti‐MYC approaches. The combination of targeting kRAS and MYC downregulation in OV56 cells did not offer any advantage over focused anti‐kRAS approaches, and effects on cisplatin potentiation were modest. Surprisingly, SKOV‐3 cells were relatively unaffected by knocking down either kRAS or MYC, alone or in combination, yet they were significantly more responsive to cisplatin‐induced cell death when both oncogenes were modulated. The potentiating effects of targeted oncogene knockdown are under investigation for paclitaxel and doxorubicin in all cell lines, as is a more aggressive approach to knockdown in SKOV‐3 cells. This program feeds into our efforts to modulate the transcription of either MYC or kRAS through their promoter non‐B‐DNA secondary structures, termed G‐quadruplexes (G4s), with lead therapeutics identified for each oncogene. Moreover, as the oncogene targets are validated, combination therapies are under development for liposomal encapsulation with the G4‐targeting therapeutic for either, or both, oncogene, and standard chemotherapies.

This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.