Repurposed drug shows promise for resistant lung cancer

By Naveed Saleh, MD, MS
Published February 23, 2021

Key Takeaways

One of the main challenges in treating lung cancer is EGFR-TKI resistance. In a preclinical study published in Cancer Medicine, researchers assessed whether targeting YAP-p62 signaling and the use of the YAP inhibitor verteporfin can suppress EGFR-TKI resistance in lung adenocarcinoma. 

EGFR-TKIs (epidermal growth factor receptor [EGFR] tyrosine kinase inhibitors [TKIs]) are a standard treatment for advanced non-small cell lung cancer patients with EGFR-activating mutations. The researchers utilized PC9, PC9/GR, and HCC827/GR cell lines to assess the activation of autophagy and EGFR-TKI resistance, with chloroquine applied as an autophagic blocker, and verteporfin, a YAP inhibitor. (Verteporfin is typically used with laser light therapy to treat serious eye conditions such as macular degeneration and others.)

“We tried to reveal the effect of autophagy adaptor p62 which is accumulated by autophagy inhibitor in EGFR-TKI-resistant lung adenocarcinoma,” the authors wrote. “We identified that p62 has oncogenic functions that induce cell proliferation and invasion of EGFR-TKI-resistant lung adenocarcinoma.”

The investigators discovered that YAP regulates p62 transcription via ERK, and inhibiting YAP thwarts oncogenic p62 expression. Furthermore, they confirmed that YAP and p62 expression are positively correlated in patients with EGFR-mutant lung adenocarcinoma. 

The researchers treated EGFR-TKI-resistant cancer patients with the YAP inhibitor verteporfin to arrest cell survival by means of manipulating the YAP-p62 axis. They found that this agent killed EGFR-TKI-resistant lung cancer cells by lowering the expression of oncogenic p62, YAP, and its target PD-L1. The researchers noted that the “cumulative effect of oncogenic p62 should be considered when using autophagy inhibitors, especially drugs that act at the last stage of autophagy such as chloroquine and bafilomycin A1.”

Cellular stresses including serum starvation or increased metabolic demand can trigger autophagy. Autophagy is an emerging focus of study as a drug target overcoming immunotherapy drug resistance.

Autophagy is known to have opposed, context-dependent functions in cancer, and works as a tumor suppressor before the establishment of a tumor by breaking down misfolded proteins. On the other hand, in established cancer cells, the activation of autophagy facilitates survival versus chemo- and radiotherapy. 

Recent research has demonstrated that autophagy inhibitors including hydroxychloroquine and chloroquine helped restore chemosensitivity by interfering with the fusion between autophagosome and lysosome, with clinical trials employing drugs that target autophagy as mono- or combination therapy currently underway.

Some studies have demonstrated that autophagy inhibitors are efficacious in treatment-resistant patients, although adverse effects arise including retinopathy and gastrointestinal problems induced by hydroxychloroquine and chloroquine. Of note, proper indications for these drugs have yet to be elucidated. 

In some contexts, p62 displays oncogenic function, thus maintaining an appropriate concentration of p62 helps prevent tumorigenesis and inhibits cancer progression. Normally, p62 expression is moderated by signals from oxidative stress, JNK, ERK, and NRF2. When p62 accumulates in autophagic-defective cells, it can lead to genomic instability and tumorigenesis by interacting with oncogenic signals.

The Hippo pathway is integral in tumorigenesis, metastasis, and epithelial mesenchymal transition. The Hippo effector YAP imparts EGFR-TKI resistance by many mechanisms including the upregulating AXL and ERK activation in lung cancer. Recent research has shown that YAP can mediate the transcription of PD-L1. FDA-approved verteporfin, which interrupts the YAP/TEAD interaction, could show promise in surmounting chemoresistance in certain cases.  

The interaction between YAP and autophagy is currently a hot topic, with some studies indicating that YAP activates autophagy to boost cancer cell survival or cisplatin resistance. Conversely, another study indicated that autophagy regulates carcinogenesis and differentiation of liver cells by the break-down of YAP. Nevertheless, these patterns of interaction are context-dependent, thus the relationship between YAP and p62 is still unknown.

“We suggest that targeting YAP-p62 signaling axis can be useful to suppress the EGFR-TKI-resistant lung cancer,” the authors concluded. “Therefore, drug repurposing of verteporfin for lung cancer treatment may be valuable to consider because it can inhibit critical targets: p62, YAP, and PD-L1 at the same time.”

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