Tailoring treatment of nonsmall cell lung cancer by tissue type: role of pemetrexed

Abstract

Pemetrexed (ALIMTA, LY231514, MTA) is a novel multitargeted antifolate that is currently approved for the treatment of metastatic nonsmall cell lung cancer (NSCLC). Recent evidence reveals that the drug's efficacy is limited to nonsquamous lung cancer histology. As we further understand the drug's mechanisms of action, new genomic and proteomic evidence is shedding light on why some patients respond while others do not. The first goal of this review is to briefly review pemetrexed's mechanism of action, resistance patterns, toxicity profile, and pharmacokinetics. We will also review the clinical trials that led to its use in NSCLC, with special attention to data showing that pemetrexed has greater efficacy in nonsquamous histologies of NSCLC. Furthermore, we will discuss the hypotheses for the genomic and proteomic basis for this variation in efficacy. Finally, we will report the future directions for pemetrexed as a personalized agent for nonsquamous NSCLC.

Keywords: antifoliate; nonsmall cell lung cancer; pemetrexed.

Figure 1

Targets for pemetrexed in folate metabolism. Pemetrexed is transported into the cell via the reduced folate carrier (RFC), folate receptor-α (FRα), and the low pH transporter. The drug is transferred out of the cell by the multidrug resistance protein (MRP) through an efflux mechanism. Once inside the cell, the drug is polyglutamated into its more active form by folylpolyglutamate synthase (FPGS). The polyglutamated derivatives of pemetrexed strongly inhibit thymidylate synthase (TS), thus disrupting the transformation of deoxyuridine monophosphate (dUMP) to deoxythymidine monophosphate (dTMP). The drug also causes secondary inhibition of glycinamide ribonucleotide formyltransferase (GARFT), aminoimidazole caroxamide ribonucleotide formyltransferase (AICARFT), and DHFR. Inhibition of GARFT and AICARFT decreases de novo purine biosynthesis, while inhibition of DHFR inhibits tetrahydrafolate (THF) synthesis. Abbreviations: PRPP, phosphoribosyl pyrophosphate; GAR, glycinamide ribonucleotide; fGAR, N-formylglycinamide ribonucleotide; AICAR, 5-aminoimidazole-4-caroxamide ribonucleotide; fAICAR, 5-formylaminoimidazole-4-caroxamide ribonucleotide; IMP, inosine monophosphate.