All cancers are defined by the unrestrained growth of cells, leading to tumor growth and metastasis. But what makes some cancers respond well to treatment, and not others? Identifying the genetic background of the cancer is often a crucial first step towards devising an effective treatment that exploits its unique vulnerabilities.
Some squamous cell carcinomas—such as those in the head, neck and lung—are known to respond poorly to standard treatment, in addition to being notoriously aggressive. Now, a multi-disciplinary effort with collaborators from A*STAR’s Bioinformatics Institute (BII) and Genome Institute of Singapore (GIS) has discovered why these aggressive carcinomas behave the way they do.
It turns out that a variant of the cancer-associated MET gene, called METN375S, is responsible for a subset of aggressive squamous cell carcinoma. This polymorphism was previously reported among certain ancestries, including South Asians and East Asians, and among 11% of the Singaporean population.
“Using germline DNA samples and medical history from cancer patients, we managed to confirm that METN375S is correlated to poorer prognosis in head and neck squamous cell carcinoma and lung squamous cell carcinoma,” said study co-author Chandra Verma, a Senior Principal Investigator at BII. The study, published in Nature Communications, was conducted by Li Ren Kong, a Research Fellow at the Cancer Science Institute of Singapore with a team led by Boon Cher Goh of the National University Health System (NUHS).
Because the tumors associated with this variant did not respond to c-MET inhibitors, which are the standard treatment for inhibiting oncogenic c-MET kinase activity, there has been a lack of interest in pursuing METN375S as a predictive biomarker in the clinic.
A thorough molecular dissection of METN375S to understand how this variant can cause such aggressive tumors revealed that this c-MET mutant codes for a variant that binds with high affinity to a receptor kinase called human epidermal growth factor receptor 2 (HER2).
Once bound, the METN375S/HER2 dimer activates HER2 signaling in a ligand-independent fashion, sending out cues for tumor cells to proliferate, invade and metastasize rapidly. The result: aggressive squamous cell carcinoma.
Verma and Srinivasaraghavan Kannan at BII were able to model this phenomenon using computer simulations. Their simulations showed that HER2 remains active even in the presence of c-MET inhibitors, which explains why the tumors never responded well to c-MET inhibitors.
Instead of targeting c-MET, their data suggest that targeting HER2 may be a better option for inhibiting HER2 signaling. “Treatment with HER2 inhibitors is able to shut down the METN375S/HER2-induced axis and suppress tumor cell growth and invasiveness,” Verma said.
Clinical trial recruitment has begun for patients with the METN375S polymorphism, who will receive daily treatment with a pan-HER2 inhibitor drug called afatinib. “National University Hospital is currently screening for and recruiting patients who carry the METN375S variant,” Kong revealed.
The A*STAR-affiliated researchers contributing to this research are from the Genome Institute of Singapore (GIS) and the Bioinformatics Institute (BII).
