Cancer mutation profiles predict ICIs efficacy in patients with non-small cell lung cancer

Abstract

Although immune checkpoint inhibitors (ICIs) have produced remarkable responses in non-small cell lung cancer (NSCLC) patients, receivers still have a relatively low response rate. Initial response assessment by conventional imaging and evaluation criteria is often unable to identify whether patients can achieve durable clinical benefit from ICIs. Overall, there are sparse effective biomarkers identified to screen NSCLC patients responding to this therapy. A lot of studies have reported that patients with specific gene mutations may benefit from or resist to immunotherapy. However, the single gene mutation may be not effective enough to predict the benefit from immunotherapy for patients. With the advancement in sequencing technology, further studies indicate that many mutations often co-occur and suggest a drastic transformation of tumour microenvironment phenotype. Moreover, co-mutation events have been reported to synergise to activate or suppress signalling pathways of anti-tumour immune response, which also indicates a potential target for combining intervention. Thus, the different mutation profile (especially co-mutation) of patients may be an important concern for predicting or promoting the efficacy of ICIs. However, there is a lack of comprehensive knowledge of this field until now. Therefore, in this study, we reviewed and elaborated the value of cancer mutation profile in predicting the efficacy of immunotherapy and analysed the underlying mechanisms, to provide an alternative way for screening dominant groups, and thereby, optimising individualised therapy for NSCLC patients.

Development of 10-Hydroxycamptothecin-crizotinib conjugate based on the synergistic effect on lung cancer cells

“…For ALK, EGFR is its bypass signalling pathways and vice versa. Moreover, the mutations activate the similar intracellular signalling cascade including phosphatidylinositol 3 kinase (PI3K)/AKT, MEK/extracellular regulated protein kinases (ERK)/mitogen-activated protein kinases (MAPK), C-Jun terminal kinase (JNK), signal transducer and activator of transcription (STATs), nuclear factor-kappa B (NF-κB), and so on, resulting in DNA synthesis and cell proliferation 6 . Although the three cells used in our experiment contained different mutations, H1975 cells harbour the L858R/T790M mutation, HCC827 has an EGFR deletion mutation in exon 19, and H460 is KRAS mutation, the downstream signal pathways have changed to varying degrees.…”

“…Various driver gene mutations of NSCLC were identified nearly two decades such as epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), V-Ki-ras2 Kirsten rat sarcoma viral oncogene (KRAS), C-ros oncogene 1 (ROS1), cellular mesenchymal-to-epithelial transition (c-Met), and so on 4 . Subsequently, drugs targeting driving mutations appeared including tyrosine kinase inhibitors (TKIs) 5 and immune checkpoint inhibitors (ICIs) 6 . The targeted drugs especially EGFR tyrosine kinase inhibitors (EGFR-TKIs) bring significant benefits for the NSCLC patients harboured the mutant gene and improves the 5-year survival of patients.…”

KRAS and TP53 co-mutation predicts benefit of immune checkpoint blockade in lung adenocarcinoma

“…Mutation testing is mandatory in advanced lung adenocarcinoma because patients with actionable genetic alterations such as EGFR mutations and ALK/RET/ROS1 fusions should receive targeted therapy rather than ICI-comprising regimens in the first-line [2]. Several studies have investigated the role of oncogenic mutations in ICI response, but the influence of co-mutations in tumour suppressor genes has not been adequately studied [9]. TP53 and KRAS are the most frequently mutated genes in lung adenocarcinoma populations of Western countries being altered in about half and one-third of patients, respectively [10].…”