Lung cancer in Morocco: EGFR and PIK3CA mutations as therapeutic targets and the lack of HER2 mutations

Abstract

Lung cancer (LC) mutations in the epidermal growth factor receptor (EGFR), phosphoinositide 3-kinase catalytic subunit alpha (PIK3CA), and human epidermal growth factor receptor 2 (HER2) genes represent promising targets for personalized treatment strategies. This study aims to investigate the mutation profiles of these genes in Moroccan LC patients and examine their correlation with clinicopathological features. In this prospective study, LC specimens were collected from 60 patients. Mutations in specific regions of EGFR (exons 18 - 21), PIK3CA (exons 9 and 20), and HER2 (exon 20) were assessed using polymerase chain reaction and sequencing. Correlation with clinicopathological features was analyzed using Jamovi software. Overall, 25 patients (41.7%, 25/60) harbored mutations in EGFR, and five patients (8.3%, 5/60) had alterations in PIK3CA, while no mutation was found in HER2. Most EGFR mutations were located in exon 21 (19/27), and PIK3CA mutations were found in exons 9 and 20. Interestingly, 3.4% of cases exhibited co-occurring PIK3CA and EGFR mutations. EGFR mutations were observed across multiple histological types, whereas PIK3CA mutations were associated with adenocarcinoma and squamous cell carcinoma. No notable correlations were found between EGFR mutations and clinicopathological parameters, but a significant association between PIK3CA mutations and age was observed. The occurrence of EGFR and PIK3CA mutations highlights their potential as biomarkers for personalized LC therapy. The absence of HER2 mutations in this cohort warrants further investigation. These findings highlight the importance of expanding molecular profiling to identify additional actionable mutations for tailored treatment in LC patients.

Keywords

Lung cancer / Mutations / Biomarkers / EGFR / HER2 / PIK3CA / Target therapy

Funding

None.

Conflict of interest

All authors declare that they have no competing interests.

References

[1] Zhou Q, Meng X, Sun L, et al. Efficacy and safety of KRASG12C inhibitor IBI351 monotherapy in patients with advanced NSCLC: Results from a phase 2 pivotal study. J Thorac Oncol. 2024; 19(12):1630-1639. doi: 10.1016/j.jtho.2024.08.005

[2] Erefai O, Soulaymani A, Mokhtari A, Hami H. Clinical and histopathological pattern of lung cancer in Morocco. Pan Afr Med J. 2022; 42:283. doi: 10.11604/pamj.2022.42.283.35593

[3] Colombino M, Paliogiannis P, Cossu A, et al. EGFR, KRAS, BRAF, ALK, and cMET genetic alterations in 1440 Sardinian patients with lung adenocarcinoma. BMC Pulm Med. 2019; 19(1):209. doi: 10.1186/s12890-019-0964-x

[4] Travis WD, Brambilla E, Nicholson AG, et al. The 2015 World Health Organization classification of lung tumors: Impact of genetic, clinical and radiologic advances since the 2004 classification. J Thorac Oncol. 2015; 10(9):1243-1260. doi: 10.1097/JTO.0000000000000630

[5] Molina JR, Yang P, Cassivi SD, Schild SE, Adjei AA. Non-small cell lung cancer: Epidemiology, risk factors, treatment, and survivorship. Mayo Clin Proc. 2008; 83(5):584-594. doi: 10.4065/83.5.584

[6] Sha X, Gong G, Qiu Q, Duan J, Li D, Yin Y. Identifying pathological subtypes of non-small-cell lung cancer by using the radiomic features of 18F-fluorodeoxyglucose positron emission computed tomography. Transl Cancer Res. 2019; 8(5):1741-1749. doi: 10.21037/tcr.2019.08.20

[7] EL Founini Y, Guessous F, Dehbi H, et al. First insight into the mutational landscape of BRAF and KRAS genes in lung cancer patients from Morocco. Curr Pharmacogenomics Pers Med. 2024;Vol 22. doi: 10.2174/0118756921347352241112105112

[8] Restrepo JC, Martínez Guevara D, Pareja López A, Montenegro Palacios JF, Liscano Y. Identification and application of emerging biomarkers in treatment of non-small-cell lung cancer: Systematic review. Cancers (Basel). 2024; 16(13):2338. doi: 10.3390/cancers16132338

[9] Hu H, Zhu J, Zhong Y, et al. PIK3CA mutation confers resistance to chemotherapy in triple-negative breast cancer by inhibiting apoptosis and activating the PI3K/AKT/mTOR signaling pathway. Ann Transl Med. 2021; 9(5):410. doi: 10.21037/atm-21-698

[10] Liu X, Mei W, Zhang P, Zeng C. PIK3CA mutation as an acquired resistance driver to EGFR-TKIs in non-small cell lung cancer: Clinical challenges and opportunities. Pharmacol Res. 2024; 202:107123. doi: 10.1016/j.phrs.2024.107123

[11] Moasser MM. The oncogene HER2: Its signaling and transforming functions and its role in human cancer pathogenesis. Oncogene. 2007; 26(45):6469-6487. doi: 10.1038/sj.onc.1210477

[12] Yang Z, Tam KY. Combination strategies using EGFR-TKi in NSCLC therapy: Learning from the gap between pre-clinical results and clinical outcomes. Int J Biol Sci. 2018; 14(2): 204-216. doi: 10.7150/ijbs.22955

[13] Pretelli G, Spagnolo CC, Ciappina G, Santarpia M, Pasello G. Overview on therapeutic options in uncommon EGFR mutant non-small cell lung cancer (NSCLC): New lights for an unmet medical need. Int J Mol Sci. 2023; 24(10):8878. doi: 10.3390/ijms24108878

[14] Yarden Y, Sliwkowski MX. Untangling the ErbB signalling network. Nat Rev Mol Cell Biol. 2001; 2(2):127-137. doi: 10.1038/35052073

[15] Riudavets M, Sullivan I, Abdayem P, Planchard D. Targeting HER2 in non-small-cell lung cancer (NSCLC): A glimpse of hope? An updated review on therapeutic strategies in NSCLC harbouring HER2 alterations. ESMO Open. 2021; 6(5):100260. doi: 10.1016/j.esmoop.2021.100260

[16] Loeffler E, Ancel J, Dalstein V, Deslée G, Polette M, Nawrocki-Raby B. HER2 alterations in non-small cell lung cancer: Biologico-clinical consequences and interest in therapeutic strategies. Life (Basel). 2023; 14(1):64. doi: 10.3390/life14010064

[17] Pillai RN, Behera M, Berry LD, et al. HER2 mutations in lung adenocarcinomas: A report from the lung cancer mutation consortium. Cancer. 2017; 123(21):4099-4105. doi: 10.1002/cncr.30869

[18] Rubin E, Shan KS, Dalal S, et al. Molecular targeting of the human epidermal growth factor receptor-2 (HER2) genes across various cancers. Int J Mol Sci. 2024; 25(2):1064. doi: 10.3390/ijms25021064

[19] Zhao L, Vogt PK. Hot-spot mutations in p110alpha of phosphatidylinositol 3-kinase (pI3K): Differential interactions with the regulatory subunit p85 and with RAS. Cell Cycle. 2010; 9(3):596-600. doi: 10.4161/cc.9.3.10599

[20] Martín Martorell P, Huerta M, Compañ Quilis A, et al. Coexistence of EGFR, KRAS, BRAF, and PIK3CA mutations and ALK rearrangement in a comprehensive cohort of 326 consecutive Spanish nonsquamous NSCLC patients. Clin Lung Cancer. 2017; 18(6):e395-e402. doi: 10.1016/j.cllc.2017.04.006

[21] Tsao MS, Nicholson AG, Maleszewski JJ, Marx A, Travis WD. Introduction to 2021 WHO classification of thoracic tumors. J Thorac Oncol. 2022; 17(1):e1-e4. doi: 10.1016/j.jtho.2021.09.017

[22] Sambrook J, Fritsch ER, Maniatis T. Molecular Cloning: A Laboratory Manual. 2nd ed. Cold Spring Harbor, NY: Cold Spring Harbor Laboratory Press; 1989.

[23] Lemine Sow M, El Yacoubi H, Moukafih B, et al. Frequency and types of EGFR mutations in Moroccan patients with non-small cell lung cancer. Tumori. 2021; 107(4):335-340. doi: 10.1177/0300891620964571

[24] Paez JG, Jänne PA, Lee JC, et al. EGFR mutations in lung cancer: Correlation with clinical response to Gefitinib therapy. Science. 2004; 304(5676):1497-1500. doi: 10.1126/science.1099314

[25] Hayes TK, Aquilanti E, Persky NS, et al. Comprehensive mutational scanning of EGFR reveals TKI sensitivities of extracellular domain mutants. Nat Commun. 2024; 15(1):2742. doi: 10.1038/s41467-024-45594-4. Erratum in: Nat Commun. 2024;15(1):3273. doi: 10.1038/s41467-024-47675-w

[26] Boukansa S, Mouhrach I, El Agy F, et al. Clinicopathological and prognostic implications of EGFR mutations subtypes in Moroccan non-small cell lung cancer patients: A first report. PLoS One. 2024; 19(6):e0298721. doi: 10.1371/journal.pone.0298721

[27] Morjani O, Benkirane N, Errihani H, Elfahime EM, Lakhiari H. Molecular analysis of genetic mutations in non-small cell lung cancer in Morocco. Pan Afr Med J. 2024; 47:116. doi: 10.11604/pamj.2024.47.116.42973

[28] Da Cunha Santos G, Shepherd FA, Tsao MS. EGFR mutations and lung cancer. Annu Rev Pathol. 2011; 6:49-69. doi: 10.1146/annurev-pathol-011110-130206

[29] Patel SR, Neal JW. Adjuvant Osimertinib for resected EGFR-mutated non-small cell lung cancer: A game-changer? Transl Lung Cancer Res. 2023; 12(7):1631-1635. doi: 10.21037/tlcr-23-273

[30] Shi R, Li M, Raghavan V, et al. Targeting the CDK4/6-Rb pathway enhances response to PI3K inhibition in PIK3CA-mutant lung squamous cell carcinoma. Clin Cancer Res. 2018; 24(23):5990-6000. doi: 10.1158/1078-0432.CCR-18-0717

[31] Wang M, Li J, Huang J, Luo M. The predictive role of PIK3CA mutation status on PI3K inhibitors in HR+ breast cancer therapy: A systematic review and meta-analysis. Biomed Res Int. 2020; 2020:1598037. doi: 10.1155/2020/1598037

[32] Alqahtani A, Ayesh HSK, Halawani H. PIK3CA gene mutations in solid malignancies: Association with clinicopathological parameters and prognosis. Cancers (Basel). 2019; 12(1):93. doi: 10.3390/cancers12010093

[33] Zhang L, Shi L, Zhao X, Wang Y, Yue W. PIK3CA gene mutation associated with poor prognosis of lung adenocarcinoma. Onco Targets Ther. 2013; 6:497-502. doi: 10.2147/OTT.S41643

[34] Wang Y, Wang Y, Li J, Li J, Che G. Clinical significance of PIK3CA gene in non-small-cell lung cancer: A systematic review and meta-analysis. Biomed Res Int. 2020; 2020:3608241. doi: 10.1155/2020/3608241

[35] Kang S, Bader AG, Vogt PK. Phosphatidylinositol 3-kinase mutations identified in human cancer are oncogenic. Proc Natl Acad Sci U S A. 2005; 102(3):802-807. doi: 10.1073/pnas.0408864102

[36] Zeller KS, Idevall-Hagren O, Stefansson A, et al. PI3-kinase p110α mediates β1 integrin-induced Akt activation and membrane protrusion during cell attachment and initial spreading. Cell Signal. 2010; 22(12):1838-1848. doi: 10.1016/j.cellsig.2010.07.011

[37] Chen H, Gao W, Liu H, Sun B, Hua C, Lin X. Updates on diagnosis and treatment of PIK3CA-related overgrowth spectrum. Ann Plast Surg. 2023; 90:S209-S215. doi: 10.1097/SAP.0000000000003389

[38] Scheffler M, Bos M, Gardizi M, et al. PIK3CA mutations in non-small cell lung cancer (NSCLC): Genetic heterogeneity, prognostic impact and incidence of prior malignancies. Oncotarget. 2015; 6(2):1315-1326. doi: 10.18632/oncotarget.2834

[39] Rosell R, Karachaliou N. Co-mutations in EGFR driven non-small cell lung cancer. EBioMedicine. 2019; 42:18-19. doi: 10.1016/j.ebiom.2019.03.037

[40] Peters S, Zimmermann S. Targeted therapy in NSCLC driven by HER2 insertions. Transl Lung Cancer Res. 2014; 3(2):84-88. doi: 10.3978/j.issn.2218-6751.2014.02.06

[41] Cheng X. A comprehensive review of HER2 in cancer biology and therapeutics. Genes (Basel). 2024; 15(7):903. doi: 10.3390/genes15070903

[42] Elghissassi I, Inrhaoun H, Boukir A, et al. Frequency and spectrum of KRAS mutations in moroccan patients with lung adenocarcinoma. ISRN Oncol. 2014; 2014:192493. doi: 10.1155/2014/192493

[43] Arcila ME, Chaft JE, Nafa K, et al. Prevalence, clinicopathologic associations, and molecular spectrum of ERBB2 (HER2) tyrosine kinase mutations in lung adenocarcinomas. Clin Cancer Res. 2012; 18(18):4910-4918. doi: 10.1158/1078-0432.CCR-12-0912