Resistance to chemotherapy and molecularly targeted therapies: rationale for combination therapy in malignant melanoma

Abstract

Metastatic melanoma is one of the most intractable tumors, with all current regimens showing limited survival impact. Failure of most agents is attributed to development of therapy resistance. Accumulated evidence points to the apoptotic defect of melanoma cells and the surge of survival signals stimulated by cytotoxic drugs, as a way that tumors circumvent cytotoxic chemotherapy. An overview of inhibitors developed against these growth/survival factors, which are potential partners to be combined with systemic chemotherapy, will be discussed. The escape mechanism from molecular inhibitors also suggests a "vertical" or "horizontal" combination of molecularly targeted therapies. A better understanding of the interactions between simultaneously used regimens and of the rationale for combination therapy will provide new insights to improve survival and quality of life in patients with advanced melanoma.

Fig. 1. Potential mechanism for resistance to molecularly targeted therapies

A. Extracellular growth factors bind with cell receptors, activating a series of intricately regulated signaling. Tumor cells retain some levels of feedback inhibition, activation of one pathway might lead to inhibition of upstream substrates within the pathway, and/or the inhibition of compensatory pathways. Tumor cells depend on certain oncogenes for growth (“oncogene addiction”), these oncogene products provide good targets for molecularly targeted therapies. B. Molecular inhibitors suppress the overactivated growth/survival pathway, therefore tumors shrink. C. After prolonged treatment, induction of growth/survival signals of the same pathway and/or compensatory pathways leads to resistance against molecular inhibitors, which might be due to the disrupted feedback inhibitions. +++, overactivated signaling.