Genetic screening in Asian oral cancer cells reveals new targets

New genetic targets for improved treatment of oral squamous cell carcinomas (OSCCs) have been identified by Malaysian scientists using cutting-edge screening technologies.

Using the CRISPR-Cas9 gene editing tool, researchers from the Head and Neck Cancer Research Team at Cancer Research Malaysia (CRM) conducted genome-wide screens on 21 OSCC cell lines, 14 of which were derived from tumours of Malaysian patients with OSCC.

The team successfully identified 918 genes associated with the improved survival of cancer cells in OSCC, including some already under investigation for OSCC or other cancers (CDK6, PIK3CA, FGFR1), as well as novel genes that have yet to be explored as potential therapeutic targets. [eLife 2020;9:e57761]

“Notably, we showed that about 5 percent (45/918) of these genes are highly tractable with approved drugs, or have drugs that are in late-stage of clinical testing, demonstrating that these screens could help to prioritize drugs that could be repurposed for OSCC treatment,” said the authors.

Results from the study showed that many previously identified OSCC-related cancer genes were likely non-essential to the cancer’s survivability, and thus might have limited therapeutic value. On the other hand, potentially impactful new targets were identified, including the paralogous genes YAP1 and WWTR1 of the Hippo signalling pathway. The team found that cell lines where either of the two were impaired created a detrimental loss-of-fitness effect on the cancer cells.

“YAP1 or WWTR1 amplifications occur in approximately 19 percent of head and neck squamous cell carcinomas (YAP1: 5.5 percent, WWTR1: 14.3 percent), which puts [them] among the top five cancers with the highest amplification of these genes amongst 33 cancer types,” said the authors.

The study also found that cancerous cells from patients with a history of betel quid chewing showed unique gene dependencies, such as in the nuclear factor-κB (NF-κB) signalling pathway, that did not appear in cell lines derived from Caucasian or Asian patients who were not known to chew betel quid.

Pioneering research among Asian populations

According to Professor Dr Cheong Sok Ching, corresponding study author and senior group leader of CRM’s Head and Neck Cancer Research Team, the study marks a pioneering attempt at employing CRISPR-Cas9 gene editing tool in oral cancer research.

“Using [CRISPR-Cas9], we were able to sift through tens of thousands of genes to identify the handful that cause oral cancer cells to grow. These handful of genes are now the top list for the development of targeted treatment … that kills cancer cells while sparing normal healthy cells,” said Cheong.

“Oral cancer is more common in Asia and is the most common cause of cancer-related deaths in men in India,” said Professor Datin Paduka Dr Teo Soo Hwang, OBE, CRM’s chief scientific officer. “As we move into an era of precision medicine, we have reached a turning point where we can now use powerful technologies to develop more effective cancer therapies.”

The study was conducted in collaboration with cancer genomics experts Professor Dr Mathew Garnett and (formerly) Dr Ultan McDermott of the Wellcome Sanger Institute, UK.

“With this gene editing technology, we were able to dissect the function of cancer genes. Next, the team will leverage on these findings to conduct high-throughput testing of hundreds of anti-cancer drugs,” said Garnett, who also co-led the study. “We are delighted that through the collaboration with Cancer Research Malaysia and the Wellcome Sanger Institute, we may be able to amplify treatment options for oral cancer, especially for Asians [among whom] most cases are diagnosed.”