A one-two punch model for cancer therapy

Abstract

Malignant cells are the result of mutations in genes controlling cell proliferation, invasion, and survival. Conventional chemotherapeutic drugs were designed to target vital cellular processes, such as DNA repair and replication, cytoskeleton structure, and cell division. These processes are also critical for normal proliferating cells, that as a consequence, such drugs are associated with unavoidable toxicities. Discoveries during the last decade have identified recurrent “driver" mutations in some types of cancer. The cancer cells that harbor these genetic alterations; often exhibit dependence on an activated oncogenic pathway or protein for its sustained proliferation and survival. The mechanistic rationale of targeted approaches is to destroy the tumor by blocking aberrant cell signaling to which the cancer cell is addicted, but dispensable for healthy tissues. The targeted drugs have been designed to effectively target the oncogenically activated nodes in the major signaling pathways. These drugs have been a clinical success, and often significantly prolong the lives of individuals with cancer. Unfortunately, the initial clinical responses to targeted drugs are almost always temporary and increase progression-free survival, but this improvement does not necessarily translate into a meaningful overall survival, as acquired resistance to these drugs almost invariably develops. We have to realize the issue we are dealing with is not that there are no good drugs to inhibit targets; it is more about how to use these drugs in the optimal way to prevent or overcome drug-resistance. We must rethink how we use existing cancer drugs to optimize therapy responses. Dosing all drugs to maximum tolerated dose and combine drugs haphazardly in the hope to find more effective drug combinations should be reconsidered. We need to identify vulnerabilities of drug-resistant cancer cells and selectively target these acquired vulnerabilities. We can also consider to first trap the cancer cells into a state, such as senescence, that expose novel vulnerabilities that can be targeted. Last, but not least, we need to combine the therapies with sensitive monitoring methods to monitor clonal evolution during therapy to target these vulnerabilities optimally. This strategy appears more appealing than fighting a losing battle against the inevitable development of drug resistance.