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Molecular Mechanisms of Tumor Cell Resistance to Chemotherapy pp 69–88Cite as

Mechanisms of Resistance to Targeted B-Raf Therapies

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Part of the book series: Resistance to Targeted Anti-Cancer Therapeutics ((RTACT,volume 1))

Abstract

Targeted Cancer Therapies and Resistance Our modern search for effective cancer therapies began after the First World War and the discovery of the myelosuppressive properties of nitrogen mustards. Since that time, adjuvant and chemo-radiotherapy have become the standard of care for many cancers. These non-targeted therapies have produced remissions in many patients. As our technical capacity to target radiation to tumors and our ability to perform surgical interventions improves, it is likely that these approaches will gain in effectiveness. Nevertheless, the dose limiting toxicities of chemotherapy drugs and ionizing radiation have served to expose vulnerabilities in this clinical approach. Modern translational research has sought to develop novel, targeted approaches to cancer therapy. These new approaches are based upon our understanding of cellular growth control, and bring with them the promise of greater potency and safety. The concept of targeted cancer therapy began with the identification and characterization of growth regulatory proteins in normal cells. These proteins were initially identified in acute transforming retroviruses. During the 1970s and 1980s, investigators working in a number of laboratories learned that the transforming genes of these viruses were actually derived from the host genome. In subsequent years, investigators came to understand that biochemical or genetic inactivation of these deleterious proteins in cultured cell lines leads to tumor cell death. This new understanding led to the search for specific proteins, whose activities drive the malignant transformation process. These proteins are now referred to as druggable targets. Chemical and molecular biologists are translating their understanding of the cell proliferation control into molecular therapeutics directed at these targets. Targeted therapy development for cancer is still in its infancy. Despite this, clinical trials for a number of small molecules have provided positive outcomes in patients who may have been given dire prognoses only a few years ago. Two FDA-approved drugs, Gleevec (Novartis) and Vemurafinib (Plexxikon) have provided some of the most dramatic results. Unfortunately, these drugs have also revealed a new challenge in cancer therapy—the development of resistance and relapse. Here, we describe the B-raf growth signaling pathway associated with the development of melanoma, summarize the mechanisms associated with resistance to targeted B-raf therapies, and discuss the future of this field of inquiry.

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Abbreviations

BCR:

Breakpoint cluster region

CML:

Chronic myelogenous leukemia

Src:

The transforming gene of the Rous Sarcoma Virus (RSV), a non-receptor tyrosine kinase that represents a family of such kinases that regulate cell proliferation and play a prominent role in malignant transformation

Abl:

The transforming gene of Abelson Murine Leukemia Virus (A-MuLV). Abl is a src family kinase associated with transformation of the lymphoid compartment of the hematopoietic system

MAP:

Originally microtubule-associated protein, now also mitogen-activated protein. MAP kinases refer to a group of cytoplasmic protein kinases that act downstream of growth factor receptors to transmit proliferative signals to cells

FTI:

Farnesyl transferase inhibitor

JNK:

c-Jun N terminal kinase

PI-3K:

Phosphatidyl inositol 3′ kinase

MEK:

Mitogen activated/extracellular regulatory kinase

ERK:

Extracellular regulatory kinase

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  1. Department of Oncological Sciences, Mount Sinai School of Medicine, Room 15-20 Icahn Medical Institute, 1425 Madison Avenue, New York, NY, 10029, USA

    E. Premkumar Reddy

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Tantravahi, R.V., Hoffman, B., Premkumar Reddy, E. (2013). Mechanisms of Resistance to Targeted B-Raf Therapies. In: Bonavida, B. (eds) Molecular Mechanisms of Tumor Cell Resistance to Chemotherapy. Resistance to Targeted Anti-Cancer Therapeutics, vol 1. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-7070-0_4

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