Cell Death and Cancer Therapy: Don't Forget to Kill the Cancer Cell!

Abstract

In our current age of targeted therapies, there is understandably considerable attention paid to the specific molecular targets of pharmaceutical intervention. For a targeted drug to work, it must bind to a target selectively and impair its function. Monitoring biomarkers of the impaired target function can provide vital in vivo pharmacodynamic information. Moreover, genetic changes to the target are often the source of resistance to targeted agents. However, for the treatment of cancer, it is necessary that the therapy not only provide efficient binding and inhibition of the target, but also that this intervention reliably kills the cancer cell. In this CCR Focus section, four articles make the connection between therapies that target T-cell activation, autophagy, IAP proteins, and BCL-2 and the commitment of cancer cells to cell death. Before addressing those exciting classes of targeted therapies, however, an overview is provided to discuss cell death induced by what is arguably still the most successful set of drugs in the history of medical oncology, conventional chemotherapy.

Molecular targeting of glutaminase sensitizes ovarian cancer cells to chemotherapy

“…32,33 One approach is to still use chemotherapeutics, but combine them with one or more of the molecularly targeted agents, thereby inhibiting the specific therapeutic target while simultaneously inducing apoptosis of the tumor cell. 33 Hence, strategies that would enhance the sensitivity of cancer cells to lower doses of chemotherapeutics and abrogate intrinsic or acquired drug resistance, are of great interest in the clinic. 34,35 The high rate of death from ovarian cancer is in part due to its late stage diagnosis, high metastatic potential, and incomplete understanding of its etiology.…”

How to unleash mitochondrial apoptotic blockades to kill cancers?

“…Nonetheless, the overwhelming information could also hinder the process of turning these discoveries into clinical benefits. The ultimate goal for any therapy is to kill cancer cells, and to cure patients 115 . With apoptosis converging on the BCL-2 family to execute the killing decision, understanding BCL-2 family proteins, their interactions and their context within other singling networks, will shed light on the effectiveness of chemotherapies and optimal combinations.…”

Alternative drug sensitivity metrics improve preclinical cancer pharmacogenomics

“…Efficacy is rarely explored as a metric of drug response, even though incomplete cytostasis and fractional cell killing result in persistence of viable cells 12 that likely contributes to incomplete tumor regression and residual disease 13 . Across the gCSI dataset both potency and efficacy exhibited substantial variation, and even highly potent drugs could be inefficient at killing (Fig.…”

“…Because the ultimate purpose of antineoplastic drugs is to kill cancer cells 13 and high potency is no guarantee of good efficacy, we propose that the best drugs and most important pharmacogenomic associations are not those associated with low IC 50 values but rather those that result in the most negative GR value at clinically relevant drug concentrations (e.g. C max ).…”