NON-SMOKER'S LUNG CANCER OVERVIEW 

keywords, non-smoker's lung cancer, Tarceva, EGFR inhibitor, Iressa, non-smoker lung cancer, treatment, 

1. Incidence 

Non-smoker's lung cancer has increased in recent years, and some estimate 10% of lung cancers involve non-smokers.  They are typically non-small cell lung cancers and specifically, adenocarcinoma or broncioloalveolar cancers (BAC).   Cancer involves mutations of genes and there are multiple genes thought to be involved with cancer and lung cancer generally.   With lung cancer, one specific gene has assumed prominence and plays a prominent role, the epidermal growth factor receptor (EGFR).   Because this gene can be identified, scientists are probably closer to finding a cure, or at least effective treatment strategy for non-smoker's lung cancer, than other types.   

2. The Role of the Epidermal Growth Factor Receptor

About a decade  ago, a drug called Iressa was developed and showed modest success.  However, some patients seemed to be doing particular well.   A ground-breaking study by Lynch found that those patients who responded had a mutation in a particular gene called the epidermal growth factor receptor (EGFR).   

"Most patients with non–small-cell lung cancer have no response to the tyrosine kinase inhibitor gefitinib, which targets the epidermal growth factor receptor (EGFR). However, about 10 percent of patients have a rapid and often dramatic clinical response. The molecular mechanisms underlying sensitivity to gefitinib are unknown.  Mutations were identified in the tyrosine kinase domain of the EGFR gene in eight of nine patients with gefitinib (Iressa) responsive lung cancer, as compared with none of the seven patients with no response.  Conclusions 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. 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) 

Thus, there were two groups: an EGFR positive group with the mutation who frequently showed significant response, and another group, EGFR negative which did not have this initial response.   Further examination showed that the EGFR positive group was typically comprised of non-smokers or very slight smokers who had quit (less than 10 pack years, years smoked x packs per day).    Pao first confirmed the findings about response.  "25 of 31 (81%) tumors from individuals experiencing partial responses or marked clinical improvement while taking gefitinib or erlotinib (Tarceva) contain mutations in the EGFR TK domain. By contrast, none of 29 specimens from patients refractory to these agents had such mutations."  Pao (2).  Most mutation-positive tumors were adenocarcinomas from patients who smoked <100 cigarettes in a lifetime (“never smokers”).   Subsequent studies would confirm that most who respond are EGFR positive, and that the EGFR positive group is primarily comprised of non-smokers and light former smokers. 

3. What is EGFR 

The human body has a complex system of signaling between cells with gene duplication a normal part of this process.  Duplication is necessary for growth, repair of damaged cells and other functions.   Proteins signal other cells to initiate replication but mutation and malfunction in these growth factors are a part of cancer, as these growth factors prompt excessive and uncontrolled duplication.  The EGFR signaling pathway helps regulate growth, survival, proliferation, and differentiation in our cells.

“The epidermal growth factor receptor (EGFR) autocrine pathway contributes to a number of processes important to cancer development and progression, including cell proliferation, apoptosis, angiogenesis, and metastatic spread. The critical role the EGFR plays in cancer has led to an extensive search for selective inhibitors of the EGFR signaling pathway. .. The most promising strategies in clinical development include monoclonal antibodies to prevent ligand binding and small molecule inhibitors of the tyrosine kinase enzymatic activity to inhibit autophosphorylation and downstream intracellular signaling."  Tartora (2), See also FDA (1) .     

The receptor  has two basic parts.   The first part of the receptor is called the extracellular ligand-binding domain.  There it receives a signal from the growth factor and a process called ligand binding occurs.  Once binding occurs, a signal is sent to the second part of the receptor called the tyrosine kinase domain.  There a process called autophosphorylation occurs.   A chemical change occurs and signals are sent to other cells.   In cancer, these signals are abnormal, and thus other cells are told to duplicate are perform other aberrant functions.  "The tyrosine kinase activity of phosphorylated EGFR in cancer cells results in the phosphorylation of downstream proteins that incite cell proliferation, invasion, metastasis, and inhibition of apoptosis.  

Cancer drugs can work in two basic ways, they can try to prevent binding at the ligand-binding domain,  or prevent autophosphorylation in the tyrosine kinase.  The fact that there are two separate functions means that drugs may later be combined.  Cells both give and receive signals.  A particular growth factor is involved both by receiving abnormal signals from other cells and giving them.    

4. Response Rates with EGFR Drugs 
 
Studies over the next 5 years confirmed and amplified the basic findings in Lynch and Pao's research.   Iressa was the first EGFR drug, but Tarceva was believed more potent.  Studies found response rates of about 60% for Iressa and Tarceva for EGFR positive patients, more than double the response rate of conventional chemotherapy.    

5. EGFR Testing for Non-Smokers 

Studies found that most, not all, non-smokers were EGFR positive, and that most, but not all smokers were EGFR negative.   Lynch's group originated testing, and commercial tests are now available, to confirm the patient's EGFR status.   Samples could be secured by biopsy, possibly in a less intrusive bronchoscope, and test are being conducted for even less intrusive means of gathering genetic material. 

6. Resistance after Initial Response 

Tarceva has been a promising drug for EGFR positive patients, with many initial responses, and even some complete responses.   Sadly, the cancer has been just as creative as the scientists.  Many patients have developed resistance and the Tarceva no longer becomes effective.  Two specific mutations have been identified as the causes of resistance:  T 790M and MET.  Strategies involve testing and identifying the mutation and developing other methods of attacking EGFR, including drugs called pan-inhibitors.

7. T790M Mutation    

One cause of resistance to Tarceva is a mutation at T790M.   It appears as but a single change, a threonine-to-methionine substitution at amino acid position 790 (T790M)  "Lung cancers caused by activating mutations in the epidermal growth factor receptor (EGFR) are initially responsive to small molecule tyrosine kinase inhibitors (TKIs), but the efficacy of these agents is often limited because of the emergence of drug resistance conferred by a second mutation, T790M.  Threonine 790 is the “gatekeeper” residue, an important determinant of inhibitor specificity in the ATP binding pocket." 

        A. T790M Testing

Testing makes sense, first determine the cause of the mutation, and secondly, use a drug showing promise with that mutation.  T790M testing is now being marketed. Maheswaran (4).   "The DxS T790M Mutation Test Kit (T790M Kit) is intended for the detection of the T790M somatic mutation in the EGFR gene. The T790M kit detects the presence of a mutant thymidine base in a background of normal cytosine bases at position 2369 (3) of the EGFR gene."

8. MET Mutation 

A second cause of resistance is the MET mutation or oncogene. 

9. Strategies for Combating Tarceva Resistance 

   A. Pan-inhibitors 

Research is ongoing.  Pan-inhibitors are showing some success in cell studies in suppressing T790 resistance. Sharma explains:

 "one of the main challenges in the treatment of NSCLC is to design inhibitors that can overcome the steric interference to drug binding conferred by the T790M mutation... Previous studies from our laboratory have shown that the irreversible dual EGFR and ERBB2 inhibitors, HKI-272 (Ref. 136) and HKI-357 (Ref. 37), as well as the irreversible EGFR inhibitor EKB-569 (Ref. 137) were all able to overcome gefitinib resistance owing to T790M in cis with an L858R mutation in EGFR. Sharma (5)

"Pan  inhibitors permanently and irreversibly stop certain functioning of EGFR.   Initial cell studies have indicated these stronger inhibitors can work against the resistant cells with the mutation.  To determine whether the T790M mutation leads to resistance to EGFR inhibitors that have different molecular structures and mechanisms, we screened four commercially available EGFR inhibitors (AG1478, cetuximab, erlotinib, and CL-387,785) using cells that were transiently transfected with the delL747–S752 construct and the delL747–S752+ T790M construct. We consistently found that CL-387,785, a specific and irreversible anilinoquinazoline EGFR inhibitor, strongly inhibited EGF-induced phosphorylation  

Its success in human studies has been debatable.  There have been several trials but none sufficient impressive to move towards FDA approval.  Many of these studies did not deal solely with T790M but a variety of patients. 

While the initial studies were promising, subsequent studies indicate a combined approach utilizing the pan-inhibitor and another drug, Erbitux, may be necessary.  Attempt to hinder the initial binding and stop the phosphylation is the idea.  Here are some of the pan-inhibitors that are being tested.

  B. HKI 272

One cell study found pan-inhibitor HKI 272 effective with tumor cells in a laboratory setting, though subsequent studies have not confirmed that promise.   Ji (1)

C. BMS 690514

Only cell studies are available.  "BMS-690514, a novel panHER/vascular endothelial growth factor receptor (VEGFR) inhibitor described here, exerted antiproliferative and proapoptotic effects on NSCLC cell lines, with prominent efficacy on H1975 cells expressing the T790M mutation."  Again, this type of study is only preliminary.

D. Cause of Resistance

The latest studies suggest a combination approach.   A recent study showed promise for a combination of Cetuximab (Erbitux) and Lapatanib (Tykerp), 

"In this study, we show that a combination of lapatinib and cetuximab overcomes gefitinib resistance in NSCLC with the T790M mutation. We observed that T790M lung cancer cells were resistant to gefitinib, and Stat3 was persistently activated in the resistant cells. A reversible EGFR and HER2 TKI, lapatinib, decreased Stat3 activation by blocking heterodimerization of EGFR and HER2, which led to a modest increase in the inhibitory effect on gefitinib-resistant T790M cells. In addition to lapatinib, the anti-EGFR antibody, cetuximab, induced down-regulation of EGFR and apoptotic cell death in T790M cells. Finally, combined lapatinib and cetuximab treatment resulted in significantly enhanced cytotoxicity against gefitinib-resistant T790M cells in vitro and in vivo. Taken together, these data suggest that treatment with a combination of lapatinib and cetuximab, which induces dimeric dissociation and EGFR down-regulation, appears to be an effective strategy for treatment of patients with EGFR TKI-resistant NSCLC."

Both Erbitux and Lapatanib are FDA approved drugs, though not specifically approved for this purpose.  They can be prescribed off label if a physician chooses.     

References

keywords, non-smoker's lung cancer, Tarceva, EGFR inhibitor, Iressa, non-smoker lung cancer, treatment,

1. Lynch, Activating Mutations in the Epidermal Growth Factor Receptor Underlying Responsiveness of Non–Small-Cell Lung Cancer to Gefitinib, Vol 350: 2129-2139  May 20, 2004  

2.  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.pnas.org.

3. Yun, The T790M mutation in EGFR kinase causes drug resistance by increasing the affinity for ATP, PNAS February 12, 2008 vol. 105 no. 6 2070-2075

4. Maheswaran, Detection of Mutations in EGFR in Circulating Lung-Cancer Cells, Volume 359:366-377,
July 24, 2008  Number 4 New Eng J Med

Our book Lung Cancer and Mesothelioma (2009) is now entering its second edition.  This site contains excerpts from chapters in the Book along with articles from various sources dealing with: new treatments, gene therapy, caregiver support, insurance issues and legal questions.   

EGFR INHIBITORS TARCEVA AND IRESSA 

Tarceva and lung cancer Analysis of Tarceva, Iressa and epidermal growth factor inhibitors. Also see Iressa 
BAC and Iressa. (Discusses results with Iressa and BAC for non-smokers)
EGFR  cell test   (Review of cell tests to determine which tumors are EGFR positive and therefore responsive to Tarceva. 
Non-smoker's lung cancer (review of treatment for non-smoker's lung cancer and recent research).
HKI 272 treatment
Newsletter Overview of EGFR inhibitors
T790 mutations and pan inhibitors

keywords, EGFR, non-smoker's lung cancer, Tarceva, EGFR inhibitor, Iressa, non-smoker lung cancer, treatment,

keywords, non-smoker's lung cancer, Tarceva, EGFR inhibitor, Iressa, non-smoker lung cancer, treatment,