A long-term goal in cancer research has been to inhibit the cell cycle in tumour cells without causing toxicity in proliferative healthy tissues. The best evidence that this is achievable is provided by CDK4/6 inhibitors, which arrest the cell cycle in G1, are well-tolerated in patients, and are effective in treating ER+/HER2- breast cancer. CDK4/6 inhibitors are effective because they arrest tumour cells more efficiently than some healthy cell types and, in addition, they affect the tumour microenvironment to enhance anti-tumour immunity. We demonstrate here another reason to explain their efficacy. Tumour cells are specifically vulnerable to CDK4/6 inhibition because during the G1 arrest, oncogenic signals drive toxic cell overgrowth. This overgrowth causes permanent cell cycle withdrawal by either preventing exit from G1 or by inducing replication stress and genotoxic damage during the subsequent S-phase and mitosis. Inhibiting or reverting oncogenic signals that converge onto mTOR can rescue this excessive growth, DNA damage and cell cycle exit in cancer cells. Conversely, inducing oncogenic signals in non-transformed cells can drive these toxic phenotypes and sensitize cells to CDK4/6 inhibition. Together, this demonstrates how oncogenic signals that have evolved to stimulate constitutive tumour growth and proliferation can be driven to cause toxic cell growth and irreversible cell cycle exit when proliferation is halted in G1.
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Radionuclide therapy using alpha or beta-emitting radionuclide as payload became state-of-the-art for cancer therapy. With the improvement in dosimetric studies, development of high-affinity target molecules, and design of several novel chelating agents which provide thermodynamically stable complexes in vivo, the scope of radionuclide therapy has increased by leaps and bounds. Additionally, radionuclide therapy along with the combination of chemotherapy is gaining importance in pre-clinics, which is quite encouraging. Thus, it opens an avenue for newer cancer therapy modalities where chemotherapy, radiation therapy, and immunotherapy are unable to break the silence of tumor response. This article describes, in brief, the causes of tumor resistance and discusses the potential of radionuclide therapy to enhance tumor response.
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