**Acknowledgements**

environment and, therefore, have all the tumor-stromal interactions, such as angiogenesis

We have described two models for NSCLC in which either the continuous oncogenic activi‐ ty of Kras (Fisher *et al*, 2001) or EGFR (Politi *et al*, 2006) are prerequisites of tumor mainte‐ nance since lung tumors underwent spontaneous regression with disappearance of the oncogene by dox withdrawal. This not only shows that tumor growth critically depends on the initiating active oncogenic pathways, but it also stresses the usefulness of these oncogen‐ ic pathways as therapeutic targets. Direct tumor intervention studies with tyrosine kinase inhibitors against EGFR mutations proved to be highly effective in several *hEGFR*-transgen‐ ic mouse models. TKIs such as gefitinib, erlotinib, and HKI-272 led to complete tumor re‐ gression (Politi *et al*., 2006; Ji *et al*., 2006a,b). In addition, treatment of lung cancer with humanized anti-hEGFR antibody (cetuximab) caused a significant tumor regression (Ji *et al*., 2006a). Further studies will be needed to investigate the signaling cascades that determine

Other mouse models for NSCLC have also been used for targeted therapies. First, dox-in‐ duced overexpression of the PI3K p110α catalytic subunit PIK3CA, mutated in its kinase do‐ main (H1047R) in *CCSP-rtTA;tetO7-PIK3CA(H1047R)* mice, induces adenocarcinomas (Engelman *et al.*, 2008). Treatment of these lung tumors with NVP-BEZ235, a dual pan-PI3K and mammalian target of rapamycin (mTOR) inhibitor, caused a marked lung tumor regres‐ sion. Interestingly, when this single agent NVP6-BEZ235 was tested on lung tumors in *CCSP-rtTA;tetO7-KrasG12D* mice, no regression was observed. However, when NVP-BEZ235 was combined with MEK inhibitor ARRY-142886, significant regression of *KrasG12D* tumors occurred (Engelman *et al*., 2008). Thus, two major RAS downstream effector pathways need‐

Although *K-RAS* is mutated in ~30% of human NSCLC, direct targeting of RAS has been un‐ successful for lung cancer therapy. Many small molecules against Ras functions have been tested and farnesyl transferase inhibitors are the most marked examples of these failed at‐ tempts (Mahgoub *et al*., 1999; Omer *et al*., 2000). Recent results with lung cancer mouse mod‐ els strongly suggest that KRAS4A, and not KRAS4B is driving the onset of NSCLC. An explanation for this failure can thus be attributed to the fact that only KRAS4B is farnesylat‐ ed, but not its isoform KRAS4A. Although we still have to study if KRAS4A is important in the pathogenesis of human NSCLC, we can imagine the importance of *Kras* mouse models

The use of optimized, genetically-modified mouse models for lung cancer for therapy re‐ search necessitates sophisticated non-invasive tools to follow tumor development and re‐ sponse to therapy *in vivo*. Measurement of tumor size as a function of time is the most obvious way of doing this and existing techniques such as computed-tomography imaging or magnetic resonance imaging for small animals are now in use (Engelman *et al*., 2008; Po‐ liti *et al*., 2006). However, these techniques are time-consuming and expensive, making them less suitable for large number of animals. Other techniques, such as fluorescence imaging and bioluminescence, can be used for measuring gene expression or tumor growth *in vivo*

the sensitivity and resistance to EGFR-related tyrosine kinase interventions.

ed to be inactivated to get an irreversible regression in Ras mutated NSCLC.

in testing functional inhibitiors for KRAS4A (To *et al*., 2008).

and degradation of the tissue matrix.

48 Oncogenesis, Inflammatory and Parasitic Tropical Diseases of the Lung

K. Inoue has been supported by NIH/NCI 5R01CA106314, ACS RSG-07-207-01-MGO, and by WFUCCC Director's Challenge Award #20595. D. Maglic has been supported by DOD pre-doctoral fellowship BC100907. We thank K. Klein for editorial assistance.
