# Context-dependent rewiring of dual-function proteins in cancer: a sequential strategy to restore apoptosis

## TL;DR

This paper proposes a new cancer treatment strategy that targets dual-function proteins in a specific sequence to restore cell death mechanisms.

## Contribution

A novel sequential therapeutic strategy is proposed to restore apoptosis by targeting tumor microenvironment adaptations, Ras signaling, and p53 activity.

## Key findings

- Dual-function proteins like p53 and Ras are deregulated by both mutations and tumor microenvironment signals.
- A three-step treatment approach is suggested to dismantle TME adaptations, inhibit Ras, and restore p53.
- The strategy emphasizes biomarker-guided patient stratification and tumor-microenvironment co-evolution.

## Abstract

Resistance to programmed cell death is a defining hallmark of cancer and a persistent barrier to successful therapy. Dual-function proteins such as p53, Ras, HIF-1α, BNIP3, and NF-κB act as molecular switches that determine cell fate between apoptosis and survival. In tumors, these proteins are deregulated not only by intrinsic mutations but also by extrinsic signals from the tumor microenvironment (TME). This Mini Review critically analyzes previous therapeutic approaches, emphasizing overlooked mechanisms such as Ras-mediated suppression of p53. It proposes a sequential therapeutic strategy: first, dismantling TME adaptations (hypoxia, inflammation, protective autophagy); second, inhibiting oncogenic Ras signaling; and third, restoring p53 activity. The phased approach integrates biomarker-guided patient stratification, recognizes tumor–microenvironment co-evolution, and highlights how resistance evolves over time. Although the concept does not resolve all challenges, it outlines a rational framework for restoring apoptotic competence and provides a pathway for translational and clinical testing.