Lung cancer accounts for one of the highest numbers of cancer related deaths, and – among its disease subtypes – HER2 mutations can play a key role in tumour initiation and growth. Unfortunately no targeted therapy is yet available to treat the most common HER2 mutations.
Dr Birgit Wilding, Dr Ralph Neumueller, Dr Flavio Solca, and colleagues at Boehringer Ingelheim have been researching these HER2 mutations, and have developed drugs that inhibit the abnormal HER2 signalling driving cancer growth. One of the new inhibitors is now undergoing testing in a Phase 1 clinical trial to safely assess the potential of the drug as effective against tumours, and also reducing side-effects.
Read the original research : https://doi.org/10.1038/s43018-022-00412-y
Image source: TiliaLucida / Adobe Stock Photos
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In this podcast, we are exploring the research of Dr Birgit Wilding, Dr Ralph Neumueller, Dr Flavio Solca, and colleagues at Boehringer Ingelheim Regional Centre, Vienna. In recent preclinical studies, they have developed drugs that inhibit the abnormal Human Epidermal Growth Factor Receptor 2 (HER2) signalling that leads to tumour growth in a subset of human cancers. Their in vitro and in vivo experiments demonstrate that the compounds decrease both tumour cell proliferation and survival. HER2 is implicated in a variety of human malignancies and is the driving oncogene – a gene which can cause a normal cell to transform into a tumour cell – in a small proportion of patients with non-small-cell lung cancer, where HER2 is mutated and driving tumour activity.
Despite HER2 being a focus of therapeutic development, current therapies have adverse effects or are ineffective in shrinking tumours, especially in cases of non-small-cell lung cancer driven by HER2 aberrations. The research team’s innovative study discovered a of HER2 inhibitor compounds that are effective against tumours, and also reduce side-effects. One of the new inhibitors, is now undergoing testing in a Phase 1 clinical trial to assess safety and efficacy in patients.
ERBB Receptor Tyrosine Kinases are proteins essential for normal development and physiological function. The ERBB family of proteins consists of four members namely, Epidermal growth factor receptor or EGFR, HER2, HER3 and HER4, that to fulfil their functions. These receptors activate the mitogen-activated protein kinase and phosphoinositide 3-kinase pathways.
These two signalling pathways transmit signals from the plasma membrane of the cell into the nucleus, triggering critical cellular activities such as cell proliferation, apoptosis, survival, migration, and differentiation. Aberrant signalling can cause abnormal cell signalling leading to cancer and neurological disorders. Considering the array of pathological conditions ERBB receptors are linked to, scientists have been working tirelessly to develop inhibitors against associated mutations in cancer.
Lung cancer causes more deaths than any other type of cancer and is divided into small-cell lung cancer and non-small-cell lung cancer. Non-small-cell lung cancer accounts for most cases and has different genetic and biological root causes. In 2-3% of non-small cell lung cancer cases, HER2 is mutated and is responsible for tumour initiation and growth. Of these HER2 mutations a large proportion of them are a type of mutation known as exon 20 insertions, which are hardest to treat. Unfortunately no targeted therapy is yet available to treat these mutations.
Collectively, oncogenic HER2 aberrations cause increased HER2 signalling and enhanced kinase activity, resulting in uncontrolled proliferation of cells and blocking of programmed cell death. This initiates neoplastic transformation, which is when normal cells become cancerous, thus leading to tumour formation. Continued abnormal HER2 signalling helps sustain the tumour and so the cancer persists. In non-small-cell lung cancer, the most common exon 20 mutation causes duplication of the amino acids Y, V, M and A, therefore a primary aim is to develop inhibitors against this specific mutation.
of current HER2 therapies include: antibodies against HER2, HER2 antibody-drug conjugates, and molecules targeting the kinase function of HER2. However, despite recent advances a problem still exists in that, HER2 exon insertion are particularly difficult to develop drugs against. Such drugs need to be efficacious in targeting the hard-to-hit exon 20 insertion mutations, while remaining selective and specific only to HER2. The drugs must also spare EGFR wild type, a protein of the same protein family, as the lack of this selectivity results in unwanted dose-limiting toxicity. This is where the dose of the drug required for efficacy cannot be achieved because of associated toxic effects.
Unfortunately, several drugs in clinical trials have been associated with side effects related to these toxicities. In addition to inadequate selectivity and subsequent toxicity, current tyrosine kinase inhibitor treatments lack potency against HER2 exon 20 mutations . In patients with HER2 non-small-cell lung cancer, standard treatments of chemotherapy and immunotherapy do not show sufficient clinical activity, and tumours are not adequately shrunk. Therefore, there is an unmet treatment need for non-small-cell lung cancer patients, and other malignancies, where HER2 exon mutant genes are the cause.
To address this medical need, Dr Birgit Wilding, Dr Ralph Neumueller, Dr Flavio Solca and fellow researchers conducted a range of complex experiments using HER2 lung cancer models. They synthesised, optimised and tested a number of compounds to find the most selective and effective drug against mutant exon 20 alleles, that also overcame the toxicity issues of previous drugs targeting the kinase function of HER2.
Their ground-breaking research published in the journal, Nature Cancer, has led to the development of inhibitors specific for, and potent against, HER2 exon 20 mutant alleles while crucially sparing wildtype EGFR. In preclinical studies, the compounds exhibit efficacy against HER2 exon 20; specifically the YVMA version blocks tumour progression, while showing excellent selectivity over other kinases. Pharmacokinetics data confirmed the suitability of the compounds to be used in vivo.
Of interest, the study demonstrates that targeting the YVMA form, and not the EGFR wildtype, has the most effect in shrinking the tumour; suggesting the role of EGFR in abnormal HER2 signalling is insignificant. The team are thus hopeful that HER2 inhibitor drugs could be administered at sufficient dosages with few side effects. However, this does need to be tested, and a Phase I clinical trial using such inhibitors is doing just that.
Mechanistically, HER2 YVMA mutation causes the mitogen-activated protein kinase pathway to be more active, contributing to tumour formation. The protein SOS1 is part of this pathway. Another significant finding of the study showed that a combination treatment of an HER2 inhibitor and an SOS1 inhibitor, resulted in enhanced inhibition of abnormal signalling. The team say this finding, and other signalling pathways, are of interest and should be further investigated to identify clinically feasible combination strategies that can work together to inhibit abnormal signalling.
From this research, a clinical candidate compound that inhibits mutated HER2 receptors has been developed by Boehringer Ingelheim. The compound is undergoing testing in a clinical trial of patients with metastatic solid tumours, whose previous treatments have been unsuccessful. This ongoing Phase 1 trial is divided into two parts. The first part assesses safety, how well the drug is tolerated and its pharmacokinetic properties; while the second part evaluates efficacy of the drug in patients with non-small-cell lung cancer driven by HER2 aberrations. The trials are still ongoing but the researchers report encouraging preliminary results in both safety, tolerability, and efficacy.
The discovery of tyrosine kinase inhibitors that target HER2 exon 20 mutant alleles but spare the non-mutated EGFR wildtype launches a new era of potential treatment options for HER2-driven cancers. Non-small-cell lung cancer patients with HER2-driven disease have limited or no current effective treatment options and represent a significant unmet need. It is hoped such patients may benefit from these inhibitors pending clinical trial investigation. The team’s comprehensive research is a true example of ’Bench to Bedside’, or translational research, where laboratory discoveries are taken forward to be tested in the real world to help patients.
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