keywords, cancer lung non-smoker, non-smoker's lung cancer, why do non-smokers get lung cancer, non-smoker's lung cancer, why do non-smokers get lung cancer,  resistance and Iressa, Tarceva and lung cancer,  treatment resistance and non-smoker's lung cancer. portions excerpted from our book, Lung Cancer and Mesothelioma.  


While lung cancer is mostly associated with smoking, an estimated 10% of cancer patients have no smoking history.  Recent studies have shown their disease has distinct characteristics in terms of development and treatment.  Tremendous strides have been made in identifying the cause and treatment of lung cancer in non-smokers. 

Non-smoker's lung cancer is in many ways a different disease from smoker's cancer, with disease mechanism, treatment and results major differences.  Non-smoker's lung cancer appears to be triggered by signaling in the tyrosine kinase region of the epidermal growth factor receptor (EGFR).  Non-smokers are frequently EGFR positive while only a small percentage of overall lung cancer patients are.  None-smokers show significant responses to the drugs Tarceva and Iressa, which have limited impact upon the overall lung cancer population.  A consensus may be evolving that initial treatment of non-smoker's lung cancer should involve, 

1) an EGFR test to confirm the patient is EGFR positive,

2) treatment with Tarceva to suppress tyrosine kinase signaling at the EGFR.

This treatment is frequently initially successful with one recent study reporting response rates of 75%.  Unfortunately the clever foe that it is, the cancer frequently develops an alternative method of signalling from the EGFR which is resistant to Tarceva.  New  second stage drugs are attempting to frustrate this signaling.  Conventional chemotherapy may be ineffective because it does not directly attack EGFR signaling.  Whether chemotherapy drug increase the efficacy of Tarceva remains unclear.

keywords, cancer lung non-smoker, non-smoker's lung cancer, why do non-smokers get lung cancer, non-smoker's lung cancer. 


29.11 Areas of Genetic Damage

Initial research found non-smokers with lung cancer have damage to the tyrosine kinase area of the epidermal growth factor receptor (EGFR).  Lynch's seminal study found that this damage predicted response to Iressa, and was present almost exclusively in non-smokers and light former smokers.   Lynch (1).   "A subgroup of patients with non–small-cell lung cancer have specific mutations in the EGFR gene, which correlate with clinical responsiveness to the tyrosine kinase inhibitor gefitinib. (Iressa)  These mutations lead to increased growth factor signaling and confer susceptibility to the inhibitor. Screening for such mutations in lung cancers may identify patients who will have a response to gefitinib."  Lynch (1).   Eight of nine patients who responded to Iressa had specific identifiable tyrosine kinase damage.

These results can be contrasted with smokers' lung cancer.  After finding mutations in exons 19 and 21 of the EGFR in the non-smokers who responded to Iressa, Lynch tested samples from other lung tumors.    "We sequenced exons 19 and 21 in a total of 95 primary tumors and 108 cancer-derived cell lines, representing diverse tumor types.  No mutations were detected, suggesting that only a subgroup of cancers, in which EGFR signaling may play a critical role in tumorigenesis, harbor EGFR mutations."  Lynch (1).   Subsequent studies replicated Lynch's findings.  Pao (4).

With an identifiable genetic component prompting growth, non-smoker's lung cancer may be easier to treat.  Rather than threading the way through multiple growth factors and tumor suppressor genes, we may have only a few areas to address. 

29.12 Adenocarcinoma and Bronchioloalveolar Lung Cancer

These non-smokers generally have adenocarcinoma and bronchioloalveolar lung cancer (BAC).   Lynch (1).

29.13 Iressa (Gefitinib) and Epidermal Growth Factor Inhibitors

Iressa suppresses chemical reactions leading to cancerous signaling in the tyrosine kinase part of the epidermal growth factor receptor.   "Gefitinib targets the ATP cleft within the tyrosine kinase epidermal growth factor receptor (EGFR), which is overexpressed in 40 to 80 percent of non–small-cell lung cancers and many other epithelial cancers."  Lynch (1)

Iressa and Tareva are drugs designed for the BAC or adenocarcinoma egfr tyrosine kinase driven lung cancer many non-smokers have. “Patients with non–small-cell lung cancer who had striking responses to gefitinib had somatic mutations in the EGFR gene that would indicate the essential role of the EGFR signaling pathway in the tumor.” Lynch (1).  "Gefitinib (Iressa) and erlotinib (Tarceva) induce dramatic clinical responses in cases of non-small cell lung cancers (NSCLCs) harboring activating mutations in the EGF receptor (EGFR)."  Many of the responders to Iressa are nonsmokers with BAC or adenocarcinoma.  

29.14 Implications for Treatment

Smoking history should be a part of medical history and be considered in formulating treatment plans. We are at the point of contouring treatment plans depending upon the type of disease, smoking history, cell studies, and other factors.

29.15 Brain Metastases and Iressa

Some recent studies have suggested that Iressa alone can provide relief to nsclc patients with cranial metastases. Ishida (5). One study testing Iressa reported, “A disease control rate of 46% (objective response rate 8.7%) and 1-year survival of 29% were documented. Histology (adenocarcinoma) and a "never-smoking" history were predictive of response. “


29.21 The Problem

Some tumors in non-smokers initially respond to Tarceva or Iressa but after a period the therapy stops working.  The phenenomenon  is sometimes called MDR or multi-drug resistance.  The tumor basically acquire a mechanism to evade the cell-killing characteristics of chemotherapy and a similar phenomenon occurs with Iressa and Tarceva :

"We show that in two of five patients with acquired resistance to gefitinib or erlotinib, progressing tumors contain, in addition to a primary drug-sensitive mutation in EGFR, a secondary mutation in exon 20, which leads to substitution of methionine for threonine at position 790 (T790M) in the kinase domain. Tumor cells from a sixth patient with a drug-sensitive EGFR mutation whose tumor progressed on adjuvant gefitinib after complete resection also contained the T790M mutation. This mutation was not detected in untreated tumor samples. Moreover, no tumors with acquired resistance had KRAS mutations, which have been associated with primary resistance to these drugs. Biochemical analyses of transfected cells and growth inhibition studies with lung cancer cell lines demonstrate that the T790M mutation confers resistance to EGFR mutants usually sensitive to either gefitinib or erlotinib." Pao (11)

"Gefitinib and erlotinib induce dramatic clinical responses in cases of non-small cell lung cancers (NSCLCs) harboring activating mutations in the EGF receptor (EGFR) (, which is targeted by these competitive inhibitors of ATP binding . The effectiveness of these tyrosine kinase inhibitors may result both from alterations in the ATP cleft associated with these mutations, which lead to enhanced inhibition of the mutant kinase by these drugs, and from biological dependence of these cancer cells on the increased survival signals transduced by the mutant receptors, a phenomenon described as “oncogene addiction”.  Although therapeutic responses to both gefitinib and erlotinib can persist for as long as 2–3 years, the mean duration of response in most cases of NSCLC is only 6–8 months ."  Kwak (7)

29.211 T790 Mutation

The T790 mutation apparently develop in response to Iressa treatment and allows cancer type signalling and resistance to the drug.  

"the T790M mutation confers drug resistance not just to wild-type EGFR but also to mutant EGFRs associated with clinical responsiveness to EGFR tyrosine kinase inhibitors . Our results further demonstrate that an analogous mechanism of acquired resistance exists for imatinib and EGFR tyrosine kinase inhibitors  despite the fact that the various agents target different kinases in distinct diseases.... The T790 mutation appears In tumors from patients not treated with either gefitinib or erlotinib, the 2369 C→T mutation (T790M) appears to be extremely rare. We have not identified this mutation in 155 tumors (see above), and among nearly 1,300 lung cancers in which analysis of EGFR exons 18 to 21 has been performed."

There are a variety of possible approaches.   Initially a drug that could target T790M specifically is possible, but does not appear to be available.   See Ihle (12),  We look below at two approaches with drugs available or in clinical trials.  

29.22 Erb-2 Inhibitors

Complimenting Iressa with other EGFR inhibitors is one approach.  EGFR is part of the ERB family, and is also known as Erb1.  Drugs have targeted ERb2, and signalling occurs between Erb1 and Erb2.   Herceptin is a well-known drug used principally for breast cancer which inhibits ERB2.   Henson (8).   Kwak (7) explains, "Knockdown of ERBB2 in NCI-H1650 and its gefitinib-resistant derivatives also caused loss of viability suggesting a role for EGFR–ERBB2 heterodimers in transducing essential survival signals in tumor cells harboring
EGFR mutations. "

29.23 Irreversible Inhibitors

Like most gene associated with cancer, Erb1 has a role in normal tissue functioning.  Drugs like Iressa and Tarceva have relatively limited side effects and are reversible upon cessation of treatment.   A more dramatic approach is to permanently suppress functioning of EGFR.  This approach makes sense if it appears EGFR is playing a significant role in the cancer,  and Iressa or Tarceva have stopped working on a patient with advanced life-threatening metastatic cancer.  Kwak's cell study indicates the effectiveness of such drugs:

 "Inhibition of EGFR alone by an irreversible inhibitor seems to be sufficient to induce apoptosis (cell death) in gefitinib resistant cells, as demonstrated by the effectiveness of EKB-569, which primarily targets EGFR.... Both HKI-357 and HKI-272 were considerably more
effective than gefitinib in suppressing ligand-induced EGFR autophosphorylation and its downstream signaling, as determined
by AKT and MAPK phosphorylation (Fig. 4A). Similarly, all three irreversible inhibitors suppressed proliferation
in this cell line under conditions where it is resistant to gefitinib (Fig. 4B). Thus, irreversible ERBB inhibitors seem to
be effective in cells harboring the T790M EGFR as well as in cells with altered trafficking of the wild-type receptor. " Kwak (7)   See Rabintran (9) for prior studies with HKI 272.

A clinical trial will be testing the drug.  Wyeth (10).

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29.31 Harvard EGFR Test

Lynch provided the initial research on EGFR at Harvard and Massachusetts General Hospital, and helped formulate a test which detects the EGFR damage which predicts response to Iressa and Tarceva:

"The Harvard Medical School - Partners HealthCare Center for Genetics and Genomics (HPCGG) has begun to offer a test that gives doctors a valuable new tool to guide the treatment of certain lung cancers.

The test – known as EGFR Kinase Domain Sequencing – was developed in cooperation with the pathology laboratories of Brigham and Women’s Hospital and Massachusetts General Hospital, and detects mutations in a critical part of the gene called epidermal growth factor receptor (EGFR). The gene mutation is present in a subset of non-small cell lung cancers, most commonly adenocarcinomas and bronchoalveolar carcinomas arising in nonsmokers. When the mutation is present, it is associated with a response to the anti-cancer drug Iressa (gefitinib). Iressa works by blocking the function of the mutant EGFR protein that these cancer cells need to survive and proliferate.

Last April, two teams of investigators – one led by Thomas Lynch, MD, and Daniel Haber, MD, PhD, at Massachusetts General Hospital, and one by Bruce Johnson, MD, William Sellers, MD, and Matthew Meyerson, MD, PhD, at the Dana-Farber Cancer Institute – discovered the molecular marker that identifies lung cancer patients whose tumors will respond to Iressa. Until then, doctors had been unable to understand why Iressa caused tumors to shrink significantly in only 13.6 percent of patients, even though some of those responses were rapid and dramatic. The discovery of the EGFR mutation provided the answer.

Now, less than six months after the gene mutation discovery, the HPCGG Laboratory has prepared a molecular test to screen lung cancer tumors for the mutation. The test, which takes approximately two weeks to complete, involves extracting DNA from a tumor tissue sample. The test is significant because it gives doctors the information they need to decide which patients may benefit from Iressa at the earliest possible time, within weeks of diagnosis."

29.32 Cost and Insurance

The test costs approximately 850.  A reasonable argument can be made that this amount should be covered by insurance, where a physician prescribed the test.

Many insurers have particular laboratories.  However, because this is a new test, few will have comparable facilities.

29.33 Use

The test is useful to both include and exclude patients.  The value of Iressa or Tarceva outside the target group is at best debatable.  There is little reliable evidence to show its benefits outside this group.  A few studies have found people outside the target group who may benefit, and there was some evidence of disease stabilization even in those that do not response. 


29.41 Location of EGFR

Recent studies indicate the importance of identifying specific areas of genetic damage in cancer.  Scientists have created a genetic map identifying specific locations for genes.  EGFR is located at  7p12.  That means it is located on chromosome 7, position 12. 

29.42 Family of Genes

EGFR is part of the ERB family of tyrosine kinase receptors.  EGFR is also called  Erb1. The family comprises Erb1, Erb2 (responsive to Herceptin), Erb3, and Erb 4.

29.43 Structure

Growth factors initiate their  process by binding to and activating cell-surface receptors with tyrosine kinases.  EGFR is a receptor comprised of three basic parts: extracellular region, ligand-binding region, and tyrosine kinase. 

29.431 Extracellular Ligand Binding Domain of the EGFR    

The title is descriptive; this is a portion of the EGFR which lies outside the tyrosine kinase region.  Here is where binding occurs, where the growth factor meets the receptor. 

29.432 Tyrosine Kinase Region

Once binding occurs a signal is sent to the tyrosine kinase.   The binding of growth factors (GFs) to receptor tyrosine kinases (RTKs) activates RTK activity and initiates the formation of several protein complexes


The receptors’ intrinsic tyrosine kinase activity phosphorylates tyrosine amino acid residues in both receptors

It then signals other genes.

29.44 Function of EGFR

This receptors plays a role in the control of cellular activities including cell division, differentiation, and migration.  "The epidermal growth factor receptor (EGFR) is a cell surface receptor that directs the initiation of processes such as growth, proliferation, apoptosis, adhesion, migration, and differentiation, when it is activated by specific growth factors. Overexpression, or increased abundance, of EGFR has been reported in numerous human cancers." 

29.45 Role in Cancer

Overexpression or dysregulation of the EGFR family members has been implicated in a variety of human cancers.  Klein 16, Genetic Map 14. 

29.46 Associated Growth Factors

It would be easy to say that EGFR links with its associated growth factor Epidermal Growth Factor.  However, when it links with EGF it is also linked with Transforming Growth Factor, and potentially others.

    29.461 Cox-2

Cox-2 has been associated with carcinogenic processes and EGF is linked with Cox-2. 

keywords, cancer lung non-smoker, non-smoker's lung cancer, why do non-smokers get lung cancer, non-smoker's lung cancer. 


1. Lynch, Activating Mutations in the Epidermal Growth Factor Receptor Underlying Responsiveness of Non–Small-Cell Lung Cancer to Gefitinib, Volume 350:2129-2139, May 20, 2004 (full text available online).
2. Miller, Bronchioloalveolar pathologic subtype and smoking history predict sensitivity to gefitinib in advanced non-small-cell lung cancer, J Clin Oncol. 2004 Mar 15;22(6):1103-9.
3. Chang, Successful treatment of multifocal bronchioloalveolar cell carcinoma with ZD1839 (Iressa) in two patients, J Formos Med Assoc. 2003 Jun;102(6):407-11.
4. Pao, EGF receptor gene mutations are common in lung cancers from "never smokers" and are associated with sensitivity of tumors to gefitinib and erlotinib, Proceeding National Academy of Science, NAS September 7, 2004 , vol. 101, no. 36 13306-13311. www,
5. Ishida, Gefitinib as a first line of therapy in non-small cell lung cancer with brain metastases, Intern Med. 2004 Aug;43(8):718-20
6. Haringhuizen, Gefitinib as a last treatment option for non-small-cell lung cancer: durable disease control in a subset of patients, Ann Oncol. 2004 May;15(5):786-92.
7. Kwak, Irreversible inhibitors of the EGF receptor may circumvent acquired resistance to gefitinib, Proc Natl Acad Sci U S A. 2005 May 24; 102(21): 7665–7670 (full-text available online).  
8.  Henson, Herceptin Sensitizes ErbB2–Overexpressing Cells to Apoptosis by Reducing Antiapoptotic Mcl-1 Expression Clinical Cancer Research Vol. 12, 845-853, February 2006
9. Rabintran, Antitumor Activity of HKI-272, an Orally Active, Irreversible Inhibitor of the HER-2 Tyrosine Kinase Cancer Research 64, 3958-3965, June 1, 2004
10. Wyeth Laboratories, Study Evaluating the Safety of HKI-272 in Subjects With Advanced Non-Small Cell Lung Cancer, Identifier: NCT00266877
11. Pao, Acquired Resistance of Lung Adenocarcinomas to Gefitinib or Erlotinib Is Associated with a Second Mutation in the EGFR Kinase Domain, PLoS Med. 2005 March; 2(3): e73.
12. Ihle, The phosphatidylinositol-3-kinase inhibitor PX-866 overcomes resistance to the epidermal growth factor receptor inhibitor gefitinib in A-549 human non–small cell lung cancer xenografts Mol Cancer Ther. 2005;4:1349-1357
13. Food and Drug Administration Center for Drug Evaluation and Research Oncologic Drugs Advisory Committee Meeting- Iressa March 4, 2005
14. OMIM Genetic Map,
15., NCBI Handbook.
16.  Klein, A structure-based model for ligand binding and dimerization of EGF receptors, PNAS | January 27, 2004 | vol. 101 | no. 4 | 929-934 
17. Ludwig Institute for Cancer Research

Comments on this article are welcome.  Email

keywords, cancer lung non-smoker, epidermal growth factor inhibitor, non-smoker's lung cancer, Iressa, Tarceva, why do non-smokers get lung cancer,  resistance and Iressa, Tarceva and lung cancer,  treatment resistance and non-smoker's lung cancer.
Above is an expanded version of portions of our book dealing with lung cancer.


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