Hailed as “new ammunition in the war against cancer” and featured in TIME magazine at the turn of the new millennium, molecularly targeted therapies have gone on to revolutionize cancer treatment. Clinical responses, however, are all too often short-lived as cancer cells become resistant.
In response to this significant challenge, researchers are attempting to understand the molecular mechanisms underlying resistance. As a result, a number of “smarter” therapies are now available that are specifically designed to treat resistant tumors and novel technologies for earlier detection of resistance have begun to emerge.
Acquired Resistance Poses Substantial Challenge
Since the early 2000s, therapies designed to interfere with specific molecules that drive cancer cell growth and proliferation have been repeatedly clinically validated in the treatment of various forms of cancer. Drugs targeting the tyrosine kinase receptors that play a central role in the cancer signaling pathways that orchestrate these cellular processes have proved particularly successful.
Yet despite these advances, the 5-year survival of many patients with cancer remains poor. As with traditional anticancer therapies, a significant limitation to the success of these “smart” drugs has proved to be the rapid acquisition of resistance by cancer cells.
Resistance to targeted therapy is typically classed as either intrinsic, in which a subpopulation of cancer cells are already resistant prior to treatment, or acquired, whereby cancer cells develop mechanisms of resistance in response to drug therapy.
If targeted therapies are to achieve their full potential, the challenge of resistance must be addressed. Fortunately, although overcoming resistance to traditional therapies has been particularly challenging, the mechanism of action of targeted therapies has become better understood, which makes understanding how resistance is acquired a simpler task. The experience in non–small cell lung cancer (NSCLC) highlights the evolving understanding of the genomic drivers of the disease and resistance pathways (Figure).
Unraveling Mechanisms of Resistance
Mechanisms of resistance are being elucidated through cancer cell line models and tumor biopsy samples. Both methods compare paired samples of pretreatment, drug-sensitive cell lines/tumor samples, with posttreatment, drug-resistant ones. Thus far, the predominant mechanisms of resistance fall into two general classes: those affecting the drug target itself, which typically are secondary genetic alterations including mutation and gene amplification; and those that are independent of the drug target, which include upregulation of alternative signaling pathways that bypass the targeted pathway. Nongenetic mechanisms of resistance have also been identified, such as epigenetic modifications and changes in drug metabolism. Studies of resistance in NSCLC have also shown that the tumor may undergo changes in its histology during drug treatment that can lead to resistance.
Ultimately, these mechanisms of resistance achieve a common goal of allowing the cancer cell to maintain its intracellular growth and proliferation signaling in spite of the presence of targeted therapeutics designed to inhibit it.
Secondary Mutations: A Common Pathway to Resistance
The most commonly observed mechanisms of acquired resistance to targeted therapies involve the development of secondary genetic mutations in the drug target.Gateway Mutations
Many tyrosine kinase inhibitors (TKIs) were designed to bind to a conserved threonine residue on their target molecules. This threonine controls access to a hydrophobic pocket within the active site of the enzyme and has therefore been dubbed a gatekeeper amino acid. A single point mutation that changes this threonine to a bulkier amino acid disrupts the TKI’s ability to bind to its target.
This kind of mutation has been shown to be a highly conserved mechanism through which cancer cells develop resistance to targeted therapy. It was first observed in patients with NSCLC treated with inhibitors targeting the epidermal growth factor receptor (EGFR), such as erlotinib (Tarceva) and gefitinib (Iressa). The T790M gatekeeper mutation is present in 50% of patients who develop resistance to EGFR-targeted therapies, but is rarely found in patients with untreated tumors.
Analogous gatekeeper mutations have also been identified in the ALK gene (L1196M), which confers resistance to crizotinib (Xalkori) in patients with ALK-positive NSCLC, and in the KIT gene (T670I), which drives resistance to imatinib (Gleevec) in patients with gastrointestinal stromal tumors (GIST). Gatekeeper mutations have also been observed in the BCR-ABL fusion gene (T315I), leading to resistance to imatinib and other TKIs in patients with chronic myelogenous leukemia (CML).Other Resistance-Driving Mutations