Activation of the Integrated Stress Response in drug-tolerant melanoma cells confers vulnerability to mitoribosome-targeting antibiotics

Therapy resistance remains a major clinical challenge for the management of metastatic melanoma. Here we show that activation of the Integrated Stress Response (ISR), which we show is common in drug-tolerant and resistant melanoma, promotes selective synthesis of mitochondrial proteins in the cytosol. Since mitochondrial translation adapts to the influx of nuclear-encoded mitochondrial proteins, ISR activation indirectly enhances mitochondrial translation and makes these cells highly vulnerable to mitochondrial translation inhibitors. Treatment of melanoma with mitoribosome-targeting antibiotics, induces proteotoxic stress and significantly compromises the growth of -mutant and immunotherapy-resistant skin melanoma as well as uveal melanoma. Additionally, a triple BRAFi/MEKi/Tigecycline combination abrogates the emergence of the classical dedifferentiated drug-tolerant states and thus delayed or even prevented the development of resistance in BRAF PDX models. Consistently, a melanoma patient exposed to Doxycycline, a mitoribosome-targeting antibiotic commonly used to treat infections, experienced a complete and long-lasting response of a treatment-resistant lesion.