This table is a summary of selected “molecularly targeted” agents approved by the FDA in just over a decade. Generating such a list raises the question of what actually constitutes a molecularly targeted agent. For many investigators, the term emphasizes monoclonal antibodies and tyrosine kinase inhibitors (TKIs), as we have in this issue. However, we must recognize that frequently, for our targeted agents, the target(s) is still unknown, and further, one might argue that for older drugs, such as the taxanes and tamoxifen, the target is better defined. Regardless, this list of drugs represents a major success in its expansion of options for our patients. While imatinib revolutionized the therapy of CML and introduced an unprecedented level of optimism in the field, the reality for solid tumors is that targeted therapies have thus far had only limited success. The clinical data presented in seeking their approval remind us of the unenviable challenge the FDA confronts—such as determining whether a 10-day survival advantage warrant a drug's approval. The May 2001 issue of TIME magazine described imatinib as new ammunition in the war against cancer and as a prototype for other therapies. However, over the decade it has become evident that we are still far from identifying the magic bullet both in terms of toxicity and efficacy.

Table 1.

Molecularly targeted drugs approved by the FDA in the past decade

DrugDiseaseFDA Approval Date
Trastuzumab Breast Cancer 1998 
Ontak Cutaneous T Cell Lymphoma (CTCL) 1999 
Bexarotene CTCL 1999 
Imatinib Adult Ph+ Chronic Myelogenous Leukemia (CML) 2001 
Imatinib Gastrointestinal Stromal Tumor (GIST) 2002 
Gefitinib Non_Small Cell Lung Cancer (NSCLC) 2003 
Erlotinib NSCLC 2004 
Bevacizumab Colorectal Cancer 2004 
Cetuximab Colorectal Cancer 2004 
Letrozole Breast Cancer 2004 
Sorafenib Renal Cell Cancer 2005 
Erlotinib Pancreatic Cancer 2005 
Cetuximab Head and Neck Cancer 2006 
Panitumumab Colorectal Cancer 2006 
Sunitinib Renal Cell Cancer 2006 
Sunitinib GIST 2006 
Imatinib Pediatric Ph+ CML 2006 
Dasatinib CML 2006 
Bevacizumab NSCLC 2006 
Bevacizumab Colorectal Cancer 2006 
Vorinostat CTCL 2006 
Rituximab Diffuse Large B Cell Lymphoma 2006 
Rituximab Low Grade Lymphoma 2006 
Bortezomib Mantle Cell Lymphoma 2006 
Sorafenib Hepatocellular Carcinoma 2007 
Lapatinib Breast Cancer 2007 
Temsirolimus Renal Cell Cancer 2007 
Nilotinib CML 2007 
Bevacizumab Breast Cancer 2008 
Bevacizumab Glioblastoma 2009 
Everolimus Renal Cell Cancer 2009 
Bevacizumab Renal Cell Cancer 2009 
Pazopanib Renal Cell Cancer 2009 
Romidepsin CTCL 2009 
DrugDiseaseFDA Approval Date
Trastuzumab Breast Cancer 1998 
Ontak Cutaneous T Cell Lymphoma (CTCL) 1999 
Bexarotene CTCL 1999 
Imatinib Adult Ph+ Chronic Myelogenous Leukemia (CML) 2001 
Imatinib Gastrointestinal Stromal Tumor (GIST) 2002 
Gefitinib Non_Small Cell Lung Cancer (NSCLC) 2003 
Erlotinib NSCLC 2004 
Bevacizumab Colorectal Cancer 2004 
Cetuximab Colorectal Cancer 2004 
Letrozole Breast Cancer 2004 
Sorafenib Renal Cell Cancer 2005 
Erlotinib Pancreatic Cancer 2005 
Cetuximab Head and Neck Cancer 2006 
Panitumumab Colorectal Cancer 2006 
Sunitinib Renal Cell Cancer 2006 
Sunitinib GIST 2006 
Imatinib Pediatric Ph+ CML 2006 
Dasatinib CML 2006 
Bevacizumab NSCLC 2006 
Bevacizumab Colorectal Cancer 2006 
Vorinostat CTCL 2006 
Rituximab Diffuse Large B Cell Lymphoma 2006 
Rituximab Low Grade Lymphoma 2006 
Bortezomib Mantle Cell Lymphoma 2006 
Sorafenib Hepatocellular Carcinoma 2007 
Lapatinib Breast Cancer 2007 
Temsirolimus Renal Cell Cancer 2007 
Nilotinib CML 2007 
Bevacizumab Breast Cancer 2008 
Bevacizumab Glioblastoma 2009 
Everolimus Renal Cell Cancer 2009 
Bevacizumab Renal Cell Cancer 2009 
Pazopanib Renal Cell Cancer 2009 
Romidepsin CTCL 2009 

The mechanisms limiting efficacy are the subject of this issue of CCR Focus. Our experts examine drug resistance—to imatinib and related TKIs in CML and GIST and to erlotinib and gefitinib in lung cancer. Turning to the monoclonal antibodies, both validated and hypothesized mechanisms of resistance to cetuximab and trastuzumab are described. Our Guest Editor Lee Ellis highlights these discussions and then clarifies recent arguments about a dark side to resistance to agents such as bevacizumab. We see again the complexity of cancer and the adaptability of cancer cells. As with every issue of CCR Focus, it is our hope that the articles inform and intrigue both the expert in the field and the interested but non-expert observer.