B13 - Harnessing Cell Death Mechanisms in Cancer

Killing cancer cells through a process that awakens the immune system is a strategy with the greatest promise.

However, most anti-cancer drugs kill cancer cells by apoptosis, a caspase-enabled form of cellular suicide that tends to be immunologically silent.

Instead of killing cancer cells by apoptosis, we will test the hypothesis that killing cancer cells through necroptosis will improve therapy. Necroptosis is a lytic form of cell death during which a cell typically swells and then bursts. This form of cell death is the body’s natural strategy of killing virus infected cells.

Cells that die in this way also flood the micro-environment with small signalling molecules (danger signals and alarmins) that can trigger inflammation and attract immune cells, thereby. However, cancer cells often hijack RIPK1 kinase to block necroptosis and resist immunological detection. Importantly, RIPK1’s scaffolding but not kinase function is required for this activity.

This is because the scaffolding function of RIPK1 drives NF-kB signalling and NF-kB-dependent induction of pro-survival gene products.

Further, chronic NF-kB signalling by RIPK1 can contribute to the production of an immunosuppressive chemokine programme, leading to decreased infiltration of immune cells and profound resistance to immune checkpoint blockade.

Additionally, RIPK1’s scaffold function can also trigger sub-lethal activation of caspase-8, which in turn cleaves and inactivates RIPK3, effectively blocking necroptosis.

Here, we aim to restore the sensitivity to necroptosis and immunotherapy responsiveness by eliminating RIPK1 with the help of a RIPK1 PROTAC-degrader that we developed during our current CRUK funding period.

Approach: We will use RIPK1 PROTAC-degraders to remove the adaptor protein RIPK1 in tumours and overcome therapy resistance.

We aim to identify the mechanism of action through which acute degradation of RIPK1 results in inflammatory cell death and study how this can be exploited to boost anti-tumour immunity for patient benefit.

We will pursue the following 3 objectives: Objective 1 [WP1]: Targeting RIPK1 with PROTAC degraders to overcome resistance to cell death and anti-tumour immunity. Objective 2 [WP2]: Harnessing ERV expression to ignite anti-tumour immunity when RIPK1 is depleted.

Objective 3 [WP3]: Using patient-derived organoids and ex vivo tumour slice techniques to corroborate the effect of RIPK1 targeting in patients.

Significance of the results to cancer: Targeting RIPK1 with PROTAC degraders may ultimately translate into novel therapeutic developments to induce effective anti-tumour immunity in cancer patients.

It will also allow the identification of biomarkers for inflammatory cell death and promote immunogenic approaches to cancer treatment.