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Commentary on Pharma & Biotech Oncology / Hematology New Product Development

Posts tagged ‘EGFR’

Yesterday we discussed ELM4-ALK translocations associated with adenocarcinomas in non-small cell lung cancer (NSCLC).   Before ALK was identified, the main molecular target in this disease was EGFR mutations, which have been shown to be associated with improved responses when EGFR inhibitors such as erlotinib are given.

EGFR mutations

Although erlotinib is the EGFR inhibitor of choice in the US for patients with lung cancer who have EGFR mutations, unfortunately approx. 50% of them with development resistance as a new mutation evolves, known as T790M.  In addition, patients with EGFR mutant disease generally don’t respond well to erlotinib.

There are a number of EGFR inhibitors now in development for lung cancer, specially adenocarcinomas, and this market is rapidly getting fairly crowded, as the table shows:

EGFR Inhibitors

Note: *Although gefitinib was approved, there is very little use of this agent in the US since the FDA modified the PI to include mention of no overall survival benefit.

This table does not include all EGFR inhibitors in clinical development, since those focused on HER2+ breast and gastric cancers (trastuzumab, lapatinib, pertuzumab) and KRAS wt colorectal cancer (cetuximab and panitumumab) were excluded from this analysis. There are, no doubt, other EGFR inhibitors also being evaluated in lung cancer, but these are the main ones I’m following – it’s for illustrative purposes only!

What we can see here is that the EGFR market in lung cancer is getting pretty competitive in terms of clinical trials and is a much more mature market than the ALK one discussed yesterday, although only erlotinib is still currently available in the US for treatment of EGFR+ mutations.

Beyond that, there are at least three inhibitors in phase III trials alone:

  • Afatinib, which reported rather indifferent data in the LUX-LUNG1 trial at ESMO last September, with an improvement in response rate over placebo, but no advantage in overall survival, the primary endpoint of the trial.
  • Necitimumab, a monoclonal antibody being tested in squamous histology in combination with gemcitabine and cisplatin.
  • Nimotuzumab, another monoclonal antibody to EGFR, which is in phase III for oesophageal and H&N cancers, but currently enrolling in several phase II lung cancer trials at the moment.

Aside from the sheer awkwardness of trying to say either of the last two generic names and resorting, like many people to calling them Nessie and Nemo, I also have trouble remembering which one is which or my eyes glaze over!  The tongue twisters that are cropping up for a multitude of targeted therapies is more challenging than ever.  On top of that is the dreadful tendency of late to choose ugly brand names for cancer drugs that seem to have been purchased as a job lot from Eastern Europe brand agencies.

T790M confers resistance to erlotinib

We have known for a while that EGFR inhibitors do not work in all patients:

  • They are effective in wild type but not mutant EGFR
  • Some patients on EGFR therapy develop resistance due to a new mutation, T790M, appearing (see Hammerman et al., 2009).

There has been little progress in either of these two areas of late, although a multitude of clinical trials are now ongoing and we are awaiting data readouts.

Dr Jack West, Swedish

Dr Jack West, Swedish Cancer Institute

Dr Jack West from the Swedish Cancer Institute in Seattle blogged about his enthusiasm for the irreversible EGFR inhibitor, PF299804, in lung cancer last summer, based on the two small studies (one American and one Asian) that were reported at the time.  Another small Australian study on EGFR mutations and PF299804 was also presented at ASCO last year.

The Asian study looked promising enough at the time for Park et al., (2010) to conclude that the data from the Korean patients with KRAS wild-type NSCLC (adenocarcinoma histology) who were refractory to platinum-based chemotherapy and erlotinib (E) or gefitinib (G) that:

“Preliminary data consistent with Western trials show that in heavily treated Asian pts with NSCLC after E or G failure, PF299 is well tolerated and has antitumor activity without adversely impacting pts’ HRQOL. These results support the ongoing global P3 trial in pts with refractory NSCLC.”

KRAS mutations in NSCLC

I distinctly remember at ASCO in 2010 one of the three groups stated that a phase III trial (BR26) would be forthcoming in KRAS wt patients.  This trial is is now enrolling patients in the refractory setting after failure of erlotinib in both KRAS mutant and wild type patients, so we are unlikely to get a readout of this study before the end of 2012 at the earliest.

Dr Nathan Pennell, Taussig Cancer Center

Dr Nathan Pennell, Taussig Cancer Center

What was also interesting was another more recent post on GRACE by one of the faculty, Dr Nathan Pennell, discussing the combination of afatinib and cetuximab in EGFR+ lung cancer.

Like Dr Pennell, I would not have been enthusiastic about this potential combination after seeing the LUX-LUNG data presented by Dr Vincent Miller at ESMO last September, and knowing that cetuximab has shown weak activity in lung cancer at best, both alone and in combination with erlotinib.

However, as Dr Pennell described, the results with the afatinib plus cetuximab combination were much better than expected in erlotinib refractory lung cancer patients:

“The confirmed overall response rate in the first 45 evaluable NSCLC patients was 40%, with the response rate in the T790M patients being 50% unconfirmed (unconfirmed means they had not yet done a second set of scans to see if the tumor was still responding over 2 time points).”

Understandably, he was quietly excited by the outcome:

“This is the first time anyone has described activity for any targeted drug in the T790M EGFR population, and this provides the first glimmer of hope for the many patients out there who face the reality of knowing that their tumors are still dependent on EGFR mutations but for whom Tarceva simply doesn’t work anymore.”

This is most interesting, because while afatinib is a TKI that works similarly to erlotinib and gefitinib inside the cell on the EGFR ligand, cetuximab is a monoclonal antibody that works on the outside of the ligand, suggesting that targeting the ligand upstream and downstream may well be necessary to ensure complete EGFR inhibition in these patients ie EGFR, KRAS and T790M, we don’t know for sure, but now doubt a paper will be published soon explaining the scientific phenomenom.

The result is certainly a big surprise given the previous disappointing data for cetuximab combined with erlotinib (no responses out of 19 patients evaluated), so I’m not sure why afatinib is different given it is also a small molecule TKI.  Further large scale trials will needed to confirm these promising results.  A phase I trial with cetuximab and afatinib in NSCLC is currently enrolling patients.

For those interested, you can check out the simply stunning waterfall plot that Dr Pennell found for the combination of afatinib and cetuximab, with both EGFR+ and EGFR- patients responding.  I confess I nearly fell off my chair when I looked – the data is not what was expected at all!

Meanwhile, Pfizer also appear to be looking at PF299804 in HER2+ gastric cancer, which is logical given the activity previously demonstrated by trastuzumab.  There are over 20 studies with this pan-EGFR agent.  Although I’m sure I read somewhere that PF299804 specifically targets the T790M mutations that develop with erlotinib, it will be interesting to see what happens with wild-type and mutant subsets, since we know that erlotinib and gefitinib only work in wild type not mutant EGFR.  Another clinical trial is also enrolling patients with Pfizer’s pan-EGFR (PF299804) and MET inhibitor (crizotinib) in NSCLC.  More on c-MET inhibitors will follow in another post.

All that said, the rationale for targeting T790M mutations in erlotinib-refractory disease is fairly compelling in theory, but the trials will not be easy as there are several challenges that must be overcome:

  1. Design and implementation – patient and inhibitor selection will be crucial
  2. High risk, especially if the compound is a weak inhibitor
  3. Heavily pre-treated refractory patients tend to be sick with a higher tumour burden that is more resistant to therapy
  4. It is a small, difficult to treat subset
  5. Finding patients with good performance status who meet all the eligibility criteria is never easy in small refractory subset populations
  6. Would combinations be superior to single agent therapy or should sequencing be investigated?
  7. An upfront trial as a head to head with erlotinib would clearly be easier to execute, but also high risk if the agent is too similar

The more you look at the conundrum, the more one realises that addressing it is not as easy as it first looks.  Some basic research looking at sequencing versus combinations in cells lines and xenografts with different agents may be a useful starting point.

That said, the news last Friday that Ariad are advancing their dual EGFR-ALK inhibitor AP26113 into the clinic later this year is good news for patients with lung cancer, because more available options is always better than fewer.   It will be interesting to see how the drug fares in either ALK-refractory patients (refractory to crizotinib) or in EGFR mutations (refractory to erlotinib) as potential fast track to market strategies.

Conclusions

Overall, the landscape in lung cancer is rapidly changing as new molecular targets are being identified, along with new targeted therapies that specifically inhibit the driving cancerous activity.

EGFR mutations were the first major breakthrough in targeted therapies for lung cancer, but with the discovery of ALK translocations, T790M mutations, MET and FGFR1 ampliflication, and DDR2 mutations, we now have exciting opportunities to potentially match therapies to patients in across a range of different non-small cell lung cancer subsets in a new era of molecularly targeted and personalised therapy.

Beyond erlotinib, there is a clear high unmet medical need for new targeted therapies that specifically inhibit either the T790M mutation associated with resistance to initial therapy or will work in KRAS mutant EGFR lung cancers.  The afatinib + cetuximab combination in erlotinib refractory NSCLC looks very promising and I’m very much looking forward to watching all the new developments evolve in this area.

Disclosure: I am an unpaid member/volunteer of the GRACE Board.

References:

ResearchBlogging.orgHammerman PS, Jänne PA, & Johnson BE (2009). Resistance to Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors in Non-Small Cell Lung Cancer. Clinical Cancer Research, 15 (24), 7502-7509 PMID: 20008850

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A very apt quote from Jeff Engelman’s group caught my eye this week:

“Unfortunately, cancers invariably develop resistance, and overcoming or preventing resistance will ultimately be key to unleashing their full therapeutic potential.”

MET is the receptor tyrosine kinase for hepatocyte growth factors (HGF) and inhibition has been implicated in metastases and migration of cancer cells (Rong et al., (1994), Takayama et al., (1997)), but more recently, it has also been observed that some tumour types have MET oncogenic addiction, including gastric cancer (Smolen et al., 2006).

MET Inhibition - source: Ma et al., (2007) BJC

Qi et al., (2011) went on to explain how they were looking at strategies for overcoming resistance to MET inhibitors, using PHA-665752 and PF-2341066, as an example in highly sensitive gastric cell lines.  They investigated the possibilities in vivo and in vitro. The results, however, were unexpected:

“To our surprise, we observed at least two mechanisms of resistance that arose simultaneously.  Both resulted in maintenance of downstream PI3K (phosphoinositide 3-kinase)-AKT and MEK (MAP/ERK kinase)-ERK signaling in the presence of inhibitor.”

Many of you will be aware of activation loops from other kinases, such as imatinib (Gleevec) in CML (T315I) and GIST (D842V) or erlotinib (Tarceva) in lung cancer (T790M), and adaptive pathways e.g. with BRAF inhibitors such as PLX4032 (vemurafenib) in melanoma, so this phenomenon is not uncommon.

With the MET inhibitors tested in the current research, the group found:

  1. A mutation in the MET activation loop, Y1230
  2. Activation of the epidermal growth factor receptor (EGFR) pathway due to increased expression of transforming growth factor alpha (TGFa)

What do these results mean?

The data suggests that combining MET and EGFR inhibitors in gastric cancer may be a viable therapeutic strategy, but consideration must also be given to approaches that inhibit Y1230 mutant MET as well, in order to shut off the escape routes.

It is hard to argue with the authors conclusion that:

“These results also underscore the notion that a single cancer can simultaneously develop resistance induced by several mechanisms and highlight the daunting challenges associated with preventing or overcoming resistance.”

Given the positive results seen with trastuzumab (Herceptin) in patients with HER2-positive gastric cancer, part of me is also wondering what incremental value there would be efficacy-wise, if MET and EGFR inhibitors were used in combination with trastuzumab?  We know that the blocking the driver mutation, the adaptive pathway and the ligand is important.  Some further preclinical research in this area may shed light on the matter.

References:

ResearchBlogging.orgQi, J., McTigue, M., Rogers, A., Lifshits, E., Christensen, J., Janne, P., & Engelman, J. (2011). Multiple Mutations and Bypass Mechanisms Can Contribute to Development of Acquired Resistance to MET Inhibitors Cancer Research, 71 (3), 1081-1091 DOI: 10.1158/0008-5472.CAN-10-1623

Ma, P., Tretiakova, M., Nallasura, V., Jagadeeswaran, R., Husain, A., & Salgia, R. (2007). Downstream signalling and specific inhibition of c-MET/HGF pathway in small cell lung cancer: implications for tumour invasion British Journal of Cancer, 97 (3), 368-377 DOI: 10.1038/sj.bjc.6603884

Rong S, Segal S, Anver M, Resau JH, & Vande Woude GF (1994). Invasiveness and metastasis of NIH 3T3 cells induced by Met-hepatocyte growth factor/scatter factor autocrine stimulation. Proceedings of the National Academy of Sciences of the United States of America, 91 (11), 4731-5 PMID: 8197126

Takayama H, LaRochelle WJ, Sharp R, Otsuka T, Kriebel P, Anver M, Aaronson SA, & Merlino G (1997). Diverse tumorigenesis associated with aberrant development in mice overexpressing hepatocyte growth factor/scatter factor. Proceedings of the National Academy of Sciences of the United States of America, 94 (2), 701-6 PMID: 9012848

Smolen GA, Sordella R, Muir B, Mohapatra G, Barmettler A, Archibald H, Kim WJ, Okimoto RA, Bell DW, Sgroi DC, Christensen JG, Settleman J, & Haber DA (2006). Amplification of MET may identify a subset of cancers with extreme sensitivity to the selective tyrosine kinase inhibitor PHA-665752. Proceedings of the National Academy of Sciences of the United States of America, 103 (7), 2316-21 PMID: 16461907

AACR PI3K-mTOR special conference

Recently, while in San Francisco for the AACR special conference on the PI3K-mTOR pathway in cancer, I was particularly struck by several important learnings that have since make me think more deeply about oncology drug development going forward:

  1. With targeted therapies, we need to more carefully select the patients, based on a clearly defined patient population
  2. We need to identify both the driving mutations and the adaptive pathway
  3. Aberrant activity is often also ligand driven

This means that in the future, targeted treatment may evolve in smaller subsets of disease with more logical double or even triple combinations.  It also means that there will be more, smaller phase II trials with translational research incorporated, across multiple combinations to tease out the critical, defining protocol.  Think more adaptive trial designs similar to the BATTLE and I-Spy series in lung and breast cancer, respectively.

Of course, Pharma’s immediate reaction is going to be “oh my, that’s going to be very expensive and difficult to do with novel-novels in clinical trials!”

The reality, however, is that it may not actually be sustainable to keep charging exhorbitant prices and smart companies with deep pockets and strong commitment will build portfolios with a wide range of different targets either in house, through licensing or acquisitions.  The trend in this direction is slowly, but surely, happening as knowledge of the biology of different cancers and subsets improves.

It was therefore no surprise that two articles appeared last week in Science and Translational Medicine and piqued my interest.  Goldstein, Zong and Witte (2011) provided some thoughtful commentary on research by Ateeq et al., (2011) on the SPINK1 mutation in prostate cancer.  They observed:

The concept of one-size-fits-all therapeutics is becoming increasingly less relevant, because any one therapy is unlikely to be effective for all individuals with a complex disease such as cancer.  For the hundreds of thousands of men who are diagnosed with prostate cancer each year, their tumors do not all share the same molecular machinery, pathways, or targets.

Ateeq et al., describe how SPINK1 contributes to the aggressive phenotype.  Forced expression of recombinant SPINK1 increased prostate cancer cell proliferation and invasiveness, whereas knockdown of SPINK1 gene expression or treatment with a SPINK1-directed monoclonal antibody resulted in decreased cell division, invasiveness, and tumour growth.

SPINK1 is highly expressed in ~10% of prostate cancers, and expression has been correlated with aggressive disease.

Interestingly, SPINK1 mediated its neoplastic effects partly through interactions with the epidermal growth factor receptor (EGFR).  Ateeq et al’s experiments showed that antibodies to both SPINK1 and EGFR blocked the growth of SPINK1+/ETS tumours more than either antibody alone, and did not affect SPINK1- tumours.

In the graphic below (courtesy of Goldstein et al., 2011), you can see that in part (a) SPINK1 secreted from prostate cancer cells can stimulate EGFR dimerization, phosphorylation, and downstream signaling through phosphoinositide 3-kinase (PI3K)/AKT, mitogen-activated protein kinase (MAPK), or janus kinase (JAK) pathways in an autocrine loop.

In part (b), in addition to small-molecule agents that block AR, PI3K/AKT, MAPK, or JAK signaling pathways, monoclonal antibodies against EGFR or SPINK1 could inhibit signal transduction by blocking the physical interaction between EGFR and the SPINK1 ligand:

SPINK1 in Prostate Cancer

In the research, an approved monoclonal antibody to EGFR, cetuximab, was used, together with an un-named SPINK1 antibody with better results than either alone. We should remember though, as Goldstein et al., note:

However, disappointing results in trials of EGFR-targeted therapies for prostate cancer with gefitinib, lapatinib, or cetuximab raise doubts about the importance of the EGFR signaling pathway for most prostate cancers.

What do these results mean?

Although animal research doesn’t always translate to positive results in humans in the clinic, it is entirely possible that better patient selection and the right combinations may be necessary to target a driving mutation, ligand and adaptive pathway in order to yield better results than previously seen with EGFR inhibitors.

Overall, I think this latest research does provide a solid rationale for the development of humanised anti-SPINK1 monoclonal antibodies for targeting a subset of patients with SPINK1 positive and ETS-negative prostate cancer in clinical trials. There are mouse antibodies available for research, but I couldn’t find a humanised one in development. It will be interesting to see any company takes up the challenge going forward.

References:

ResearchBlogging.orgGoldstein, A., Zong, Y., & Witte, O. (2011). A Two-Step Toward Personalized Therapies for Prostate Cancer Science Translational Medicine, 3 (72), 72-72 DOI: 10.1126/scitranslmed.3002169

Ateeq, B., Tomlins, S., Laxman, B., Asangani, I., Cao, Q., Cao, X., Li, Y., Wang, X., Feng, F., Pienta, K., Varambally, S., & Chinnaiyan, A. (2011). Therapeutic Targeting of SPINK1-Positive Prostate Cancer Science Translational Medicine, 3 (72), 72-72 DOI: 10.1126/scitranslmed.3001498

c-MET inhibitors are a class of drug I've been interested in and following for a little while.  All are in early development and most of the big oncology players have one lurking in their pipeline. The concept of blocking c-MET is appealing because of number of studies have shown that activated c-MET mutations may be associated with poorer prognosis and induce resistance, ie an escape route for cancer cells. 

Looking at the pathways we can see MET has a strategic position in the signalling as an upstream receptor, which makes it a good potential target, much in the way EGFR, VEGF have shown proof of concept to date:

image from www.n-of-one.com
Source: n-of-one

It was therefore interesting to see a press release this morning proclaiming:

"Biotechnology company ArQule Inc said its experimental lung cancer drug showed positive results in a mid-stage trial, sending its shares up 57 percent in pre-market trade.
The drug, ARQ 197, when used with another lung cancer drug, erlotinib, showed a 66 percent improvement in median progression-free survival (PFS) – the time without cancer growth or death – in patients with advanced, refractory non-small cell lung cancer, ArQule said."

66% improvement would normally get me very enthusiastic, but after the recent glut of promising phase II data leading to flops in phase III, I'm feeling a little more cautious and circumspect.  Especially when, on further examination it appears that:

"The median PFS was 16.1 weeks in the ARQ 197 plus erlotinib arm, compared with 9.7 weeks in the erlotinib plus placebo arm, the company said in a statement.
The company, however, said the difference in PFS between the two arms did not achieve statistical significance by applying a log-rank test."

In other words, there is no significant difference between the two groups!
Hmmm, why make a lot of noise about it then?  Perhaps that's a little harsh, but achieving significance is the sine quo non of clinical trials and that's a very black and white number.  Breathless hypey press releases do make me cringe though.

I suppose we can say that these are promising, but very early, data and more time will tell whether the approach will have any meaningful impact on survival and outcomes.  Perhaps some biomarker analysis will help determine which people with non-small cell lung cancer were most likely to respond to the combination, potentially improving the efficacy and significance.

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A Pharma friend who regularly reads this blog attended the ASCO GI meeting last weekend and phoned me to say that cancer is indeed getting much more complex.  She was also highly amused at the buzzword bingo post from the AACR Molecular Targets meeting:

"Well, I just thought you might like to know that the latest buzzword bingo is 'cross-talk'"

Funnily enough, I was writing a report on cross-talk at the very moment she called.  Cross-talk occurs when two powerful signaling pathways interact, leading to interactive processes between them downstream of the original receptors.

Another Pharma buddy sent me the slides from a presentation on the Merck IGF-1R inhibitor, MK-0646, phase I results of which were reported in pancreatic cancer.  One of the focus of the presentation was 'cross-talk' according to the abstract:

"Receptor cross-talk between IGF-1R and EGFR and enhanced IGF-1R-induced activation of the PI3-kinase/Akt pathways mediate resistance to anti-EGFR agents such as erlotinib. IGF-1R + EGFR antagonists result in synergistic antitumor activity in preclinical pancreatic cancer models."

When you actually look at the pathways involved, you can see that things are indeed very complex and cross-talk is not surprising, as Pollak et al., showed in 2004:

IGF1R 

This means that inhibiting the IGF-1R pathway alone with a inhibitor such as Pfizer's figitumumab or Merck's MK-0646 is unlikely to be effective because cross-talk between the receptor and AKT/mTOR or MEK pathways may well have an impact and lead to an escape route for the cancer cells to continue surviving.  For this reason, we can see that the recent futility reported in the figitumumab lung cancer trial is not completely surprising.  However, combining the drug with an AKT or MEK inhibitor may well yield better results.

In the Merck study, the majority of patients had an objective response or stable disease when the IGF-1R inhibitor was combined with erlotinib, an EGFR inhibitor.  Cross-talk between IGF-1R and EGFR has been shown in preclinical models of pancreatic cancer. 

These early results are promising for the compound, but much work is still needed to determine suitable predictive biomarkers and ideal combinations/sequencing before moving forward into a phase III trial.

ResearchBlogging.orgPollak, M., Schernhammer, E., & Hankinson, S. (2004). Insulin-like growth factors and neoplasia Nature Reviews Cancer, 4 (7), 505-518 DOI: 10.1038/nrc1387

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It’s been a bit of a long week on lung cancer articles and while I was planning on talking about something else today, this new article in my database caught my eye:

Picture 157
Part of the reason is nostalgia – it’s 20 years ago since I finished my doctorate on early detection of preclinical lung disease and while I was interested in the methods of detecting changes in breathing patterns associated with smoking, part of me wished I’d done research on molecular biology at the time rather than applied physiology.

The reason is that I realised while doing the literature search is that biochemical and physiological changes in the airways would ultimately tell us more about early detection.

In the article above, the researchers suggest a potential mechanism by which the tobacco-specific carcinogen NNK promotes lung tumour formation and development. Now, bearing in mind that most solid tumours take years to develop from hyperplasia to full aggressive carcinoma, finding how it actually happens and why is still an inexact science, as are methods for early detection given not all smokers get lung cancer and non-smokers are not immune from the disease.

Lin et al., suggest that NNK induces the accumulation of a protein known as DNMT1 in the nucleus and that this protein silences genes that suppress tumour formation.  They offered evidence to support their hypothesis, including the observation that DNMT1 accumulates in both lung adenomas from NNK-treated mice and tumours from lung cancer patients that were smokers.  DNMT1 overexpression in lung cancer patients who smoked continuously correlated with poor prognosis.

However, the interesting part of their abstract to me was:

“We determined that in a human lung cell line, glycogen synthase kinase 3β (GSK3β) phosphorylated DNMT1 to recruit β-transducin repeat–containing protein (βTrCP), resulting in DNMT1 degradation, and that NNK activated AKT, inhibiting GSK3β function and thereby attenuating DNMT1 degradation.”

Ah, our friend AKT.  

The potential role of AKT in lung cancer came up repeatedly at last week’s AACR lung cancer meeting. The researchers there had begun to realise that blocking EGFR or IGF-1R and c-MET or AKT (either directly or indirectly via PI3K inhibition) might cut off an escape route for the cancer cell and reduce drug resistance:

Picture 159
Source:
Vivanco and Sawyers

Drs Jeffrey Engelman (MGH) and David Carbone (Vanderbilt) covered excellent quick reviews at AACR on the latest findings related to EGFR inhibition relating to c-MET and proteomics respectively.  As our knowledge of various mutations and biologic pathways improves, so does our understanding of how we can better target aberrations and treat patients with NSCLC more effectively.

Engelman’s group has just published a paper on c-MET and EGFR inhibition (see references).  They noticed that rare MET-amplified cells exist in some EGFR-mutant lung cancers before treatment. What makes the research relevant to this overview is that MET amplification activates ERBB3/PI3K/AKT signaling in EGFR mutant lung cancers and causes resistance to EGFR kinase inhibitors. They demonstrated that MET activation by its ligand, HGF, induces drug resistance through GAB1 signaling. Using high-throughput FISH analyses in both cell lines and in patients with lung cancer, they identified subpopulations of cells with MET amplification prior to drug exposure.

The concept that HGF induces resistance to tyrosine kinase inhibitors in EGFR-addicted cancers is a novel one.  They saw that HGF accelerates MET amplification by expanding preexisting MET-amplified cells. What was particularly relevant though was that analysis of pretreatment cancers identified those poised to become MET amplified, thereby offering a way to segment NSCLC patients for more personalised treatment, increasing the chances of better response rates, longer overall survival and improved patient outcomes.

Then came the killer statement:

“EGFR kinase inhibitor resistance, due to either MET amplification or autocrine HGF production, was cured in vivo by combined EGFR and MET inhibition.”

Oh my.  This leaves us seriously wondering what will happen in practice by combining erlotinib (Tarceva) or gefitinib (Iressa) with a MET inhibitor in patients with NSCLC?  Tang et al., reported some promising preclinical work in 2008 (see references) but solid data in human patients has yet to be reported.

 

I can’t wait for ASCO this year to find out!

References:

ResearchBlogging.orgLin, R., Hsieh, Y., Lin, P., Hsu, H., Chen, C., Tang, Y., Lee, C., & Wang, Y. (2010). The tobacco-specific carcinogen NNK induces DNA methyltransferase 1 accumulation and tumor suppressor gene hypermethylation in mice and lung cancer patients Journal of Clinical Investigation DOI: 10.1172/JCI40706

Vivanco, I., & Sawyers, C. (2002). The phosphatidylinositol 3-Kinase–AKT pathway in human cancer Nature Reviews Cancer, 2 (7), 489-501 DOI: 10.1038/nrc839 

Massion, P. (2004). Early Involvement of the Phosphatidylinositol 3-Kinase/Akt Pathway in Lung Cancer Progression American Journal of Respiratory and Critical Care Medicine, 170 (10), 1088-1094 DOI: 10.1164/rccm.200404-487OC

Turke, A., Zejnullahu, K., Wu, Y., Song, Y., Dias-Santagata, D., Lifshits, E., Toschi, L., Rogers, A., Mok, T., & Sequist, L. (2010). Preexistence and Clonal Selection of MET Amplification in EGFR Mutant NSCLC Cancer Cell, 17 (1), 77-88 DOI: 10.1016/j.ccr.2009.11.022

Tang, Z., Du, R., Jiang, S., Wu, C., Barkauskas, D., Richey, J., Molter, J., Lam, M., Flask, C., Gerson, S., Dowlati, A., Liu, L., Lee, Z., Halmos, B., Wang, Y., Kern, J., & Ma, P. (2008). Dual MET–EGFR combinatorial inhibition against T790M-EGFR-mediated erlotinib-resistant lung cancer British Journal of Cancer, 99 (6), 911-922 DOI: 10.1038/sj.bjc.6604559

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