Tumor and host factors that may limit efficacy of chemotherapy in non-small cell and small cell lung cancer

Abstract

While chemotherapy provides useful palliation, advanced lung cancer remains incurable since those tumors that are initially sensitive to therapy rapidly develop acquired resistance. Resistance may arise from impaired drug delivery, extracellular factors, decreased drug uptake into tumor cells, increased drug efflux, drug inactivation by detoxifying factors, decreased drug activation or binding to target, altered target, increased damage repair, tolerance of damage, decreased proapoptotic factors, increased antiapoptotic factors, or altered cell cycling or transcription factors. Factors for which there is now substantial clinical evidence of a link to small cell lung cancer (SCLC) resistance to chemotherapy include MRP (for platinum-based combination chemotherapy) and MDR1/P-gp (for non-platinum agents). SPECT MIBI and Tc-TF scanning appears to predict chemotherapy benefit in SCLC. In non-small cell lung cancer (NSCLC), the strongest clinical evidence is for taxane resistance with elevated expression or mutation of class III beta-tubulin (and possibly alpha tubulin), platinum resistance and expression of ERCC1 or BCRP, gemcitabine resistance and RRM1 expression, and resistance to several agents and COX-2 expression (although COX-2 inhibitors have had minimal impact on drug efficacy clinically). Tumors expressing high BRCA1 may have increased resistance to platinums but increased sensitivity to taxanes. Limited early clinical data suggest that chemotherapy resistance in NSCLC may also be increased with decreased expression of cyclin B1 or of Eg5, or with increased expression of ICAM, matrilysin, osteopontin, DDH, survivin, PCDGF, caveolin-1, p21WAF1/CIP1, or 14-3-3sigma, and that IGF-1R inhibitors may increase efficacy of chemotherapy, particularly in squamous cell carcinomas. Equivocal data (with some positive studies but other negative studies) suggest that NSCLC tumors with some EGFR mutations may have increased sensitivity to chemotherapy, while K-ras mutations and expression of GST-pi, RB or p27kip1 may possibly confer resistance. While limited clinical data suggest that p53 mutations are associated with resistance to platinum-based therapies in NSCLC, data on p53 IHC positivity are equivocal. To date, resistance-modulating strategies have generally not proven clinically useful in lung cancer, although small randomized trials suggest a modest benefit of verapamil and related agents in NSCLC.

Fig 1

Cell kill by first order kinetics gives a straight line in sensitive cells. Deficiency of a factor needed for tumor cell killing (“saturable passive resistance”) gives a terminal plateau on the dose-response curve, analogous to non-competitive inhibition of drug effect. Alteration or mutation of a factor (“non-saturable passive resistance”) results in a decreased dose-response curve slope (analogous to decreased affinity of a drug for its receptor). Excess of a mutation factor (“active resistance”) gives a shoulder on a dose-response curve, analogous to competitive inhibition of drug effect.

Fig. 2

Drug effect may be decreased by a decrease in drug bioavailability, hepatic activation, penetration across vessel endothelium or interstitium, uptake across cell membranes, or intracellular activation, or by decrease in tumor blood flow or oxygenation.

Fig. 3

Drug intracellular concentration may be decreased by efflux pumps, or drug may be detoxified by various factors.

Fig. 4

Drug-induced DNA damage may be repaired by various DNA repair pathways, or apoptosis may be triggered as a result of attempted repair of platinum-induced damage by the Mismatch Repair pathway. Drug effect can also be reduced due to increased, decreased or mutated target.

Fig. 5

Drug resistance can also occur due to deficient or defective proapoptotic factors or due to antiapoptotic effects of growth factors, growth factor receptors, signaling pathways, various membrane components, chaperones, transcription factors and cell cycle factors. Tumor cells are most sensitive to platinums during G1 and to taxanes during G2.