Does Molecular Profiling of <i>KRAS</i>-Mutant Non-Squamous Non-Small Cell Lung Cancer (NSCLC) Help in Treatment Strategy Planning?
Background: Several studies suggest that patients with <i>KRAS</i>-mutant NSCLC fail to benefit from standard systemic therapies and do not respond to EGFR inhibitors. Most recently, <i>KRAS</i> 12c data suggest specific treatment for improving ORR and OS. There is a clear ne...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2022-07-01
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| Series: | Current Oncology |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1718-7729/29/7/379 |
| Summary: | Background: Several studies suggest that patients with <i>KRAS</i>-mutant NSCLC fail to benefit from standard systemic therapies and do not respond to EGFR inhibitors. Most recently, <i>KRAS</i> 12c data suggest specific treatment for improving ORR and OS. There is a clear need for therapies specifically developed for these patients. Moreover, data that might be suggestive of a response to specific therapies, such as BRCA1, are needed, and two mutations that were studied in other malignancies show more response to PARP inhibitors. Molecular profiling has the potential to identify other potential targets that may provide better treatment and novel targeted therapy for KRAS-mutated NSCLC. Methods: We purified RNA from archived tissues of patients with stage I and II NSCLC with wild-type (<i>wt</i>) and mutant (<i>mt</i>) <i>KRAS</i> tumors; paired normal tissue adjacent to the tumor from 20 and 17 patients, respectively, and assessed, using real-time reverse transcriptase–polymerase chain reaction (RT-PCR), the expression of four genes involved in DNA synthesis and repair, including thymidylate synthase (TS), BRCA1, ECCR1, RAP80, and the proto-oncogene SRC. Additionally, we assessed the expression of PD-L1 in <i>mt</i> <i>KRAS</i> tumors with immunohistochemistry using an antibody against PD-L1. Results: Our results show that in <i>mt</i><i>KRAS</i> tumors, the level of expression of ERCC1, TS, and SRC was significantly increased in comparison to paired normal lung tissue (<i>p</i> ≤ 0.04). The expression of BRCA1 and RAP80 was similar in both <i>mt</i> <i>KRAS</i> tumors and paired normal tissue. Furthermore, the expression of BRCA1, TS, and SRC was significantly increased in <i>wt</i> <i>KRAS</i> tumors relative to their expression in the normal lung tissue (<i>p</i> < 0.044). The expression of ERCC1 and RAP80 was similar in <i>wt</i> <i>KRAS</i> tumors and paired normal tissue. Interestingly, SRC expression in <i>mt</i><i>KRAS</i> tumors was decreased in comparison to <i>wt</i> <i>KRAS</i> tumors. Notably, there was an expression of PD-L1 in the tumor and stromal cells in a few (5 out of 20) <i>mt</i><i>KRAS</i> tumors. Our results suggest that a greater ERCC1 expression in <i>mt</i> KRAS tumors might increase platinum resistance in this group of patients, whereas the greater expression of BRCA1 in <i>wt</i> <i>KRAS</i> tumor might be suggestive of the sensitivity of taxanes. Our data also suggest that the combination of an SRC inhibitor with a TS inhibitor, such as pemetrexed, might improve the outcome of patients with NSCLC and in particular, patients with <i>wt</i> <i>KRAS</i> tumors. PD-L1 expression in tumors, and especially stromal cells, suggests a better outcome. Conclusion: <i>mt</i> <i>KRAS</i> NSCLC patients might benefit from a treatment strategy that targets KRAS in combination with therapeutic agents based on pharmacogenomic markers, such as SRC and BRCA1. <i>mt</i><i>KRAS</i> tumors are likely to be platinum-, taxane-, and pemetrexed-resistant, as well as having a low level of PD-L1 expression; thus, they are less likely to receive single-agent immunotherapy, such as pembrolizumab, as the first-line therapy. <i>wt</i> <i>KRAS</i> tumors with BRCA1 positivity tend to be sensitive to taxane therapy and, potentially, platinum. Our results suggest the need to develop targeted therapies for <i>KRAS</i>-mutant NSCLC or combine the targeting of oncogenic <i>KRAS</i> in addition to other therapeutic agents specific to the molecular profile of the tumor. |
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| ISSN: | 1198-0052 1718-7729 |