Rapamycin Differentially Impacts Germline Stem Cell Quiescence Across Diverse Genetic Backgrounds of Drosophila Melanogaster

In response to ionizing radiation, stem cells enter a state of temporary quiescence, safeguarding the stem cell pool for tissue regeneration. Quiescence requires the inhibition of mTORC1, a kinase complex that promotes growth and suppresses autophagy, and cell cycle re-entry requires the reactivation of mTORC1. The pharmacological inhibition of mTORC1 in quiescent stem cells by rapamycin prevents cell cycle re-entry and subsequent tissue regeneration. It is well established that pharmacological responses can vary across genetic backgrounds, however, the extent to which genetic variation can impact the quiescence response to rapamycin is unclear. Here, we tested the sensitivity of stem cell quiescence to rapamycin in different genetic backgrounds within the Drosophila Genetic Reference Panel. These analyses revealed substantial variation across different genetic backgrounds, indicating that genetic variation can modulate drug-induced effects on stem cell dynamics. Our analyses suggest that mitophagy, rather than DNA damage response, is associated with the persistence of quiescence and delayed tissue regeneration by rapamycin. This work underscores the critical role of genetic background in determining drug efficacy, highlighting important implications for the therapeutic application of rapamycin.