It is likely that some of the mutations that occur late during evolution, whether passenger mutations or passenger mutations, are likely only tolerated (let alone advantageous to the cancer cell) because of the mutations that preceded them. If so, targeting mutations that occur early during tumor evolution should selectively kill cancer cells by unmasking the otherwise deleterious effects of subsequent mutations. There are now many precision cancer drugs that target such early mutations, including EGFR inhibitors for lung cancer, c-Kit mutations for GI stromal tumors, and B-Raf inhibitors for B-Raf mutant melanomas. Inactivation of the von Hippel-Lindau tumor suppressor protein (pVHL) is an early event in kidney cancer. Inactivated proteins can sometimes be tackled by exploiting epistatic relationships or synthetic lethality. For example, pVHL suppresses the HIF2 transcription factor, which in turn regulates VEGF. VEGF inhibitors are now mainstays of kidney cancer treatment. HIF2 was viewed as “undruggable”, but undruggable proteins can sometimes be targeted by allosteric modulators or degraders. A first-in-class allosteric HIF2 inhibitor has advanced to phase 3 trials based on promising early data. Most cancer drugs work better in the frontline setting, and a recent study of previously untreated von Hippel-Lindau disease patients strongly suggests this will be true for the HIF2 inhibitor. Combination therapy will be required to cure most cancer. It is tempting to combine drugs that have interdependent actions in an attempt to achieve synergy, but this increases the risk of cross-resistance. The classical way to prevent resistance is to combine drugs that have distinct mechanisms of action (to minimize toxicity and cross-resistance). In this regard, immunotherapy has emerged as a powerful modality to treat cancer cells, and complements therapies aimed at inducing cancer cell death. Both kidney cancer and melanomas are highly immunogenic and can respond to immune checkpoint blockade, yet kidney cancer has a much lower mutational burden than melanoma. Recent work suggests that kidney cancers promiscuously express endogenous retroviruses, which might serve as a source of neoantigens. If true, it might be possible to pharmacologically enhance ERV expression to augment immunotherapy.

Citation Format: William George Kaelin. (Re)emerging principles of cancer therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr PL03-02.