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Turning the Tables on Lung Cancer by Targeting STAT3 Signalling

Scientists have discovered the underlying pathways of chemotherapy resistance in non-small cell lung cancers (NSCLCs) and identified a new molecule with promising potential to overcome chemotherapy resistance and exert anti-tumour activity.

Claiming 140,000 lives annually in America alone, lung cancer is one of the most prevalent and aggressive forms of cancer, infamous for its poor prognosis and high resistance rate. One form of lung cancer, known as non-small cell lung cancer (NSCLC), is especially prevalent, making up about 80 per cent of all cases.

On a molecular level, NSCLC has been discovered to develop as a result of abnormal gene expressions and genetic mutations of epidermal growth factor receptors (EGFRs), which control cellular and tumour growth. Consequently, many anti-cancer drugs like gefitinib, which specifically targets the EFGR, have been developed.

However, like all medications, resistance to gefitinib is inevitable. As such, scientists have been investigating the underlying mechanisms of gefitinib resistance with the hopes of finding clues to prevent or overcome this resistance.

A joint study by researchers from the First Affiliated Hospital of Bengbu Medical College, China Pharmaceutical University, and Jiangnan University, has discovered a new small molecule, known as LL1, that is capable of exerting anti-tumour activity and reversing gefitinib resistance.

Previous works have shown that LL1 is capable of blocking STAT3 and exerting anti-tumour activity and selectivity. LL1 reportedly prevents the binding of the SH2 domain, a crucial domain needed to activate the STAT3 protein. STAT3 is a signal transducer and transcription activator protein that is highly associated with the pathogenesis of various cancers including pulmonary cancer. By blocking the activation of STAT3, downstream signalling pathways that normally support tumour growth and invasion can be effectively disrupted.

Pharmacological and biochemical studies have validated its inhibitive potential, but LL1 has more to bring to the table.

It was recently discovered that suppressing STAT3 activity using LL1 can also reverse the sensitivity of gefitinib-resistant cells. The team grew gefitinib-resistant A549 and PC-9 cell lines and examined their sensitivity to gefitinib using MTT assay. Based on their findings, downregulating or silencing STAT3 using LL1 increases the sensitivity of these previously resistant cells to gefitinib, hence demonstrating the remarkable potential LL1 has to restore gefitinib sensitivity in lung cancer cells.

Their results have also unlocked the underlying mechanisms of gefitinib resistance, pinpointing the activation of the STAT3/ZEB1 pathway as a major contributor to its development. ZEB1 was also identified as a mediator involved in STAT3 induced-gefitinib resistance. The team observed that downregulating ZEB1 raises the sensitivity of lung cancer cells to gefitinib and prevents cell invasion and migration. Fortunately, LL1 is also able to exert its inhibitory effects on ZEB1.

This discovery is expected to revolutionise current practices of chemotherapy and open new doors to the development of superior chemotherapeutic adjuvants. Researchers believe that LL1 can pave the way to achieve targeted cancer therapy with low risks of toxicity and suggest the use of LL1 as an alternative strategy to inhibit STAT3 and treat cases of NSCLC with acquired resistance to gefitinib. [APBN]

Source: Liu et al. (2021). Targeting STAT3 signaling overcomes gefitinib resistance in non-small cell lung cancer. Cell Death & Disease, 12(6), 1-12.