CCNE1 Amplification and PKMYT1 Inhibition Are Synthetic Lethal

Targeting of the amplification of the CCNE1 locus in ovarian cancer, despite being detected in approximately 20% of tumors, continues to be an unmet clinical need. In these overexpressing tumors, cyclin E is considered to be undruggable; however, targeting CDK2 has shown promise with current inhibitors beginning to enter clinical development. Gallo, Young, Fourtounis, and colleagues sought to provide an alternative strategy for targeting CCNE1-amplified tumors using synthetic lethality vulnerabilities induced by increased cyclin E levels by conducting a genome-scale CRISPR–Cas9-based synthetic lethality screen. Five genes, ANAPC15, FBXW7, PKMYT1, UBE2C, and UBE2S, were identified as reducing the fitness of cancer cells with CCNE1 amplification, with PKMYT1 being shown to have the most robust dependency. Using a structure-guided medicinal chemistry technique, a selective PKMYT1 inhibitor, RP-6306, was identified, with CCNE1-high cell lines demonstrating sensitivity to this drug, indicating the synthetic lethality of genetic loss of PKMYT1 can be recapitulated with pharmacologic inhibition. Moreover, both genetic and pharmacologic PKMYT1 inhibition in high CCNE1–expressing tumor cells led to DNA damage, and additional studies demonstrated that the lethality of PKMYT1 inhibition is due to activation of CDK1 as well, as it contributes to premature mitotic entry in CCNE1-high cells. Furthermore, mutations in genes that are members of the MYBL2–MMB–FOXM1 complex were found to contribute to RP-6306 resistance, and investigation into the efficacy of RP-6306 in vivo supported its ability to reduce tumor growth both alone and in combination with gemcitabine, with more durable responses observed with the combination. Overall, this study shows, using a genome-scale genetic interaction screen, that targeting PKMYT1, a vulnerability observed in CCNE1-overexpressing tumors, through use of the discovered RP-6306 inhibitor suppresses cancer growth and suggests that use of these types of screens could aid in furthering identification of oncology drug targets that drive more durable antitumor responses.

Gallo D, Young JTF, Fourtounis J, Martino G, Álvarez-Quilón A, Bernier C, et al. CCNE1 amplification is synthetic lethal with PKMYT1 kinase inhibition. Nature 2022;604:749–56.

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