In 2012, Dr. Rene Bernards of The Netherlands Cancer Institute in Amsterdam and colleagues used a CRISPR-based synthetic lethality genetic screen and found that BRAF mutant colon cancers did not respond to BRAF inhibitors because BRAF inhibition led to activation of epidermal growth factor receptor (EGFR), which maintains cell viability when BRAF is inhibited (https://bit.ly/2WmHBUU).
"We demonstrated that a combination of BRAF and EGFR inhibitors leads to effective tumor control for this group of cancers," Dr. Bernards told Reuters Health by email. "This drug combination became FDA- and EMA-approved in 2020."
In the current study, he said, "we focused on why liver cancer patients only experience modest clinical benefit from treatment with lenvatinib. We again performed a synthetic lethality CRISPR screen and again found that EGFR activation is the problem."
However, he added, the study also shows that "patients who have progressed on lenvatinib therapy still benefit from a combination of lenvatinib and gefitinib (an EGFR inhibitor)."
"The take-home message is that rational drug combinations identified through genetic screens are far more likely to deliver clinical benefit than the 'trial and error' approaches that we often see in the clinic today," he noted.
As Dr. Bernards noted, for this Nature study, his team used a CRISPR-Cas9 genetic screen and found that EGFR is synthetic lethal with lenvatinib in liver cancer. The combination of geftinib and lenvatinib showed potent anti-proliferative effects in experiments in liver cancer cell lines that express EGFR in vivo; in xenograft liver cancer cell lines; and in immunocompetent mouse models as well as patient-derived liver cancer tumors in mice.
Further, 12 patients with advanced liver cancer who were unresponsive to lenvatinib treatment showed meaningful clinical responses after treatment with lenvatinib plus geftinib. Specifically, after 4-8 weeks of combination treatment, four patients had a partial response, four had stable disease and four showed disease progression.
The authors note, "As early tumor response is closely associated with survival outcome of patients with HCC, our initial clinical responses may signal future responses in terms of long-term survival."
Dr. Bernards said, "The FDA approval of the BRAF+EGFR cocktail took eight years from discovery to approval, so we have some work ahead of us, but the hardest part has been done. I am convinced that when all trials are completed, this therapy will become a standard treatment for liver cancer patients."
Dr. Satdarshan (Paul) Monga, UPMC endowed chair and Chief of Experimental Pathology Division, and Director of the Pittsburgh Liver Research Center at the University of Pittsburgh, commented in an email to Reuters Health, "The authors do a good job in elucidating the mechanism of 'escape' of liver cancer cells from lenvatinib. These findings are predictable due to well appreciated redundancy in tyrosine kinases such that inhibition of one often leads to activation of another, both in physiological and pathological contexts."
"Identifying such redundancy is important on a case-to-case basis," he said, "but the clinical data presented to support their findings is too preliminary to make any global conclusions."
Some of the patients in the trial had received anti-PD-1 therapy as well as lenvatinib, he noted. "This is important since immunotherapy can cause delayed therapeutic response, and decreased tumor burden can occur months after the initial treatment. Hence, the response to some cases could in part or wholly be due to the PD-1 inhibitor."
Another caveat, he said, is that "since HCC often happens in patients with a preexisting liver condition, there is always ongoing regeneration that allows non-tumor liver to continue to maintain function. Several of these tyrosine kinase pathways are important in regeneration, and when you are inhibiting more than one pathway, liver function could be theoretically compromised. Hence, the cases need careful monitoring."
"A large well-designed trial will be essential to address efficacy and safety before this therapy could be advocated widely, especially since immunotherapy in combination with other inhibitors are already showing promise in HCC treatment," Dr. Monga concluded.
SOURCE: https://go.nature.com/2UXoNeF Nature, online July 21, 2021.
By Marilynn Larkin
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