Lung cancer and melanoma are responsible for almost 25% of cancer deaths in Australia. Despite recent progress with targeted and immuno-therapies, the 5 year survival rate in late stage patients is still<20%. CHK1 inhibitors are being investigated as chemosensitising agents with agents that increase replication stress, primarily Gemcitabine. Clinical trials of this combination have shown good responses but also high levels of normal tissue toxicity. Here we have investigated the molecular basis of sensitivity to CHK1 inhibitors in combination with subclinical doses of hydroxyurea (HU) in melanoma and non-small cell lung cancer (NSCLC) tumour spheres and cell lines in 2% O2 conditions and xenograft models. We report that low dose HU increased the sensitivity in more than 70% of both melanoma and NSCLC cell lines to CHK1 inhibitor (GDC-0575), triggered apoptosis and complete loss of viability with clinically achievable doses of this combination. Similar sensitivity was observed in xenograft models of both melanoma and NSCLC. We also demonstrate that a low dose of Gemcitabine combination with CHK1 inhibitor results in complete loss of proliferative potential in normal tissue, whereas normal tissue retains its proliferative potential after treatment with even high doses of hydroxyurea in combination with CHK1 inhibitor. In vivo, this translates to minimal effect on lymphocyte populations in the blood. The combination also triggers an inflammatory response involving the recruitment of macrophages, associated with increased HMGB1 nuclear and cytoplasmic staining and activation of the cGAS-STING pathway. These data indicate that the combination of low dose HU and CHK1 inhibitor have strong anti-cancer activity in the setting of melanoma and NSCLC, and triggers an inflammatory response, and is better tolerated than current combinations with Gemcitabine. Our data suggest a significant proportion of melanoma and lung cancer patients could benefit from treatment with this drug combination.