The Role of Mutations in -Mutated Non-Small-Cell Lung Cancer: Clinical Significance and Implications for Therapy

Overview

Journal Cancers (Basel)

Publisher MDPI

Specialty Oncology

Date 2022 Mar 10

PMID 35267450

Authors

Matteo Canale

Kalliopi Andrikou

Ilaria Priano

Paola Cravero

Luigi Pasini

Milena Urbini

Angelo Delmonte

Lucio Crino

Giuseppe Bronte

Paola Ulivi

Affiliations

Soon will be listed here.

Abstract

Non-Small-Cell Lung Cancer (NSCLC) is the primary cause of cancer-related death worldwide. Oncogene-addicted patients usually benefit from targeted therapy, but primary and acquired resistance mechanisms inevitably occur. Tumor protein 53 () gene is the most frequently mutated gene in cancer, including NSCLC. mutations are able to induce carcinogenesis, tumor development and resistance to therapy, influencing patient prognosis and responsiveness to therapy. mutants present in different forms, suggesting that different gene alterations confer specific acquired protein functions. In recent years, many associations between different mutations and responses to Epidermal Growth Factor Receptor () targeted therapy in NSCLC patients have been found. In this review, we discuss the current landscape concerning the role of mutants to guide primary and acquired resistance to Tyrosine-Kinase Inhibitors (TKIs) -directed, investigating the possible mechanisms of mutants within the cellular compartments. We also discuss the role of the mutations in predicting the response to targeted therapy with EGFR-TKIs, as a possible biomarker to guide patient stratification for treatment.

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References

Miyauchi E, Inoue A, Kobayashi K, Maemondo M, Sugawara S, Oizumi S . Efficacy of chemotherapy after first-line gefitinib therapy in EGFR mutation-positive advanced non-small cell lung cancer-data from a randomized Phase III study comparing gefitinib with carboplatin plus paclitaxel (NEJ002). Jpn J Clin Oncol. 2015; 45(7):670-6. DOI: 10.1093/jjco/hyv054. View

Jackman D, Pao W, Riely G, Engelman J, Kris M, Janne P . Clinical definition of acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors in non-small-cell lung cancer. J Clin Oncol. 2009; 28(2):357-60. PMC: 3870288. DOI: 10.1200/JCO.2009.24.7049. View

Nakagawa K, Nadal E, Garon E, Nishio M, Seto T, Yamamoto N . RELAY Subgroup Analyses by EGFR Ex19del and Ex21L858R Mutations for Ramucirumab Plus Erlotinib in Metastatic Non-Small Cell Lung Cancer. Clin Cancer Res. 2021; 27(19):5258-5271. PMC: 9662911. DOI: 10.1158/1078-0432.CCR-21-0273. View

La Fleur L, Falk-Sorqvist E, Smeds P, Berglund A, Sundstrom M, Mattsson J . Mutation patterns in a population-based non-small cell lung cancer cohort and prognostic impact of concomitant mutations in KRAS and TP53 or STK11. Lung Cancer. 2019; 130:50-58. DOI: 10.1016/j.lungcan.2019.01.003. View

Mok T, Wu Y, Thongprasert S, Yang C, Chu D, Saijo N . Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med. 2009; 361(10):947-57. DOI: 10.1056/NEJMoa0810699. View

Rachiglio A, Fenizia F, Piccirillo M, Galetta D, Crino L, Vincenzi B . The Presence of Concomitant Mutations Affects the Activity of EGFR Tyrosine Kinase Inhibitors in EGFR-Mutant Non-Small Cell Lung Cancer (NSCLC) Patients. Cancers (Basel). 2019; 11(3). PMC: 6468673. DOI: 10.3390/cancers11030341. View

Planchard D, Loriot Y, Andre F, Gobert A, Auger N, Lacroix L . EGFR-independent mechanisms of acquired resistance to AZD9291 in EGFR T790M-positive NSCLC patients. Ann Oncol. 2015; 26(10):2073-8. DOI: 10.1093/annonc/mdv319. View

Schlereth K, Heyl C, Krampitz A, Mernberger M, Finkernagel F, Scharfe M . Characterization of the p53 cistrome--DNA binding cooperativity dissects p53's tumor suppressor functions. PLoS Genet. 2013; 9(8):e1003726. PMC: 3744428. DOI: 10.1371/journal.pgen.1003726. View

Maciejowski J, Li Y, Bosco N, Campbell P, de Lange T . Chromothripsis and Kataegis Induced by Telomere Crisis. Cell. 2015; 163(7):1641-54. PMC: 4687025. DOI: 10.1016/j.cell.2015.11.054. View

10.

Kruiswijk F, Labuschagne C, Vousden K . p53 in survival, death and metabolic health: a lifeguard with a licence to kill. Nat Rev Mol Cell Biol. 2015; 16(7):393-405. DOI: 10.1038/nrm4007. View

11.

Offin M, Chan J, Tenet M, Rizvi H, Shen R, Riely G . Concurrent RB1 and TP53 Alterations Define a Subset of EGFR-Mutant Lung Cancers at risk for Histologic Transformation and Inferior Clinical Outcomes. J Thorac Oncol. 2019; 14(10):1784-1793. PMC: 6764905. DOI: 10.1016/j.jtho.2019.06.002. View

12.

Min S, Kim K, Kim S, Cho H, Lee Y . Chromatin-remodeling factor, RSF1, controls p53-mediated transcription in apoptosis upon DNA strand breaks. Cell Death Dis. 2018; 9(11):1079. PMC: 6197202. DOI: 10.1038/s41419-018-1128-2. View

13.

Cross D, Ashton S, Ghiorghiu S, Eberlein C, Nebhan C, Spitzler P . AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer. Cancer Discov. 2014; 4(9):1046-61. PMC: 4315625. DOI: 10.1158/2159-8290.CD-14-0337. View

14.

Ulivi P, Petracci E, Canale M, Priano I, Capelli L, Calistri D . Liquid Biopsy for EGFR Mutation Analysis in Advanced Non-Small-Cell Lung Cancer Patients: Thoughts Drawn from a Real-Life Experience. Biomedicines. 2021; 9(10). PMC: 8533402. DOI: 10.3390/biomedicines9101299. View

15.

Zhang R, Tian P, Chen B, Wang T, Li W . The prognostic impact of TP53 comutation in EGFR mutant lung cancer patients: a systematic review and meta-analysis. Postgrad Med. 2019; 131(3):199-206. DOI: 10.1080/00325481.2019.1585690. View

16.

Volckmar A, Leichsenring J, Kirchner M, Christopoulos P, Neumann O, Budczies J . Combined targeted DNA and RNA sequencing of advanced NSCLC in routine molecular diagnostics: Analysis of the first 3,000 Heidelberg cases. Int J Cancer. 2019; 145(3):649-661. DOI: 10.1002/ijc.32133. View

17.

Chmielecki J, Foo J, Oxnard G, Hutchinson K, Ohashi K, Somwar R . Optimization of dosing for EGFR-mutant non-small cell lung cancer with evolutionary cancer modeling. Sci Transl Med. 2011; 3(90):90ra59. PMC: 3500629. DOI: 10.1126/scitranslmed.3002356. View

18.

Kosaka T, Yatabe Y, Onozato R, Kuwano H, Mitsudomi T . Prognostic implication of EGFR, KRAS, and TP53 gene mutations in a large cohort of Japanese patients with surgically treated lung adenocarcinoma. J Thorac Oncol. 2008; 4(1):22-9. DOI: 10.1097/JTO.0b013e3181914111. View

19.

Xu M, Johnson D, Grandis J . EGFR-targeted therapies in the post-genomic era. Cancer Metastasis Rev. 2017; 36(3):463-473. PMC: 5693744. DOI: 10.1007/s10555-017-9687-8. View

20.

Jamal-Hanjani M, Wilson G, McGranahan N, Birkbak N, Watkins T, Veeriah S . Tracking the Evolution of Non-Small-Cell Lung Cancer. N Engl J Med. 2017; 376(22):2109-2121. DOI: 10.1056/NEJMoa1616288. View