Page 245 - EJMO-9-1

Eurasian Journal of Medicine and
Oncology
EGFR and PIK3CA mutations in lung cancer patients

1. Introduction (PIK3CA), which play pivotal roles in tumor growth,
metastasis, and therapeutic resistance. 3,9-11
Lung cancer (LC) remains a major global public health
challenge and the leading cause of cancer-related EGFR mutations are hallmark alterations in certain
mortality worldwide. In 2022, LC was the most commonly NSCLC subtypes, particularly adenocarcinomas, and
diagnosed cancer, with approximately 2.48 million new are associated with increased susceptibility to tyrosine
cases and 1.8 million deaths. Morocco ranks among the kinase inhibitors (TKIs). The majority (85 – 90%) of
1
countries with the highest LC incidence and mortality EGFR mutations, including deletions in exon 19 (ex19del)
2
within the Middle East and North Africa regions. Despite and the L858R point mutation in exon 21, exhibit high
12
significant advancements in prevention, early detection, sensitivity to EGFR inhibitors or EGFR-TKIs. The less
and therapeutic strategies, LC mortality remains a common T790M mutation in exon 20, typically absent
pressing public health issue, primarily driven by late-stage at diagnosis, is found in approximately 50% of cases that
diagnoses and the aggressive characteristics of certain develop resistance to first- and second-generation EGFR
subtypes. Histologically, LC is classified into two main inhibitors. 8,13
2-4
subtypes: Non-small cell LC (NSCLC) and small cell LC, In addition to EFGR, HER2 (also known as receptor
which differ considerably in biological behavior, prognosis, tyrosine-protein kinase ErbB2) is a tyrosine kinase
and therapeutic response. Among the NSCLC subtypes, receptor encoded by the ErbB2 proto-oncogene, located
5
adenocarcinoma is the most common (40%), followed on chromosome 17 at position 17q21. As part of the
14
by squamous cell carcinoma (25 – 30%) and large cell EGFR/ErbB family, HER2 activation occurs through
carcinoma (5 – 10%). 4,6 homo-dimerization or hetero-dimerization with other
For many years, conventional treatments such as ligand-bound HERs, triggering cross-phosphorylation
radiotherapy, chemotherapy, and surgical resection were and activating the tyrosine kinase domain. This activation
the cornerstone for managing early-stage LC. Recently, initiates a series of downstream signaling events, such as
last-generation chemotherapy drugs, in combination the extracellular signal-regulated kinase (ERK) – mitogen-
with platinum-based regimens, have slightly improved activated protein kinase, phosphatidylinositol-3-kinase
survival outcomes, raising the 5-year survival rate by (PI3K) – protein kinase B (Akt), as well as signal transducer
11%. However, chemotherapy’s inability to selectively and activator of transcription pathways, all of which
3
target tumor cells leads to severe side effects that not regulate key cellular processes, including proliferation,
only diminish the patient’s quality of life but also hinder survival, differentiation, and migration. 11,14 Dysregulation
the therapy’s overall effectiveness. These challenges of HER2, characterized by mutations (1 – 4%),
underscore the importance of exploring alternative amplifications (2 – 5%), or overexpression (2 – 30%)
15
approaches and highlight the growing interest of contributes to carcinogenesis and tumor progression in
clinicians and researchers in unraveling the molecular NSCLC and is associated with tumor progression and poor
mechanisms driving LC. clinical outcomes. 16-18
Targeting the multiple signaling pathways aberrantly Meanwhile, alterations in the gene encoding the p110α
activated in LC is a key therapeutic strategy for managing catalytic component of PI3K can cause aberrant activation
tumor progression and overcoming drug resistance. of the PI3K/AKT pathway, leading to uncontrolled cell
Moreover, the rapid increase in genomic data in oncology, proliferation and survival. In addition, these mutations
19
combined with advancements in bioinformatics tools, has are often accompanied by increased transcription of
led to the discovery of several biomarkers that support PIK3CA, elevated p110α protein levels, and enhanced
early diagnosis, therapeutic decisions, and prognosis kinase activity, further driving tumorigenesis. PIK3CA
for patients with advanced LC. Emerging research mutations are also implicated in treatment resistance and
3,7
continues to identify oncogenic driver mutations and disease recurrence, making them promising therapeutic
9
biomarkers by pinpointing genetic modifications that targets. Furthermore, the presence of concurrent
enable the development of personalized therapies. These driver mutations within the tumor significantly impacts
tailored treatments are more likely to yield positive results, therapeutic responses and survival rates in NSCLC
enhancing progression-free survival (PFS) and overall patients receiving chemotherapy or targeted therapies, as
survival (OS) while minimizing unwanted side effects. 8 these mutations can affect treatment effectiveness. 3,20

Among the most critical therapeutic targets are In Morocco, the implementation of precision medicine
genes such as epidermal growth factor receptor (EGFR), is an ongoing process that requires extensive genomic data
human epidermal growth factor receptor 2 (HER2), to explore biomarkers used for the molecular classification
and phosphoinositide 3-kinase catalytic subunit alpha of cancers and therapeutic targets. In this context, we have

Volume 9 Issue 1 (2025) 237 doi: 10.36922/ejmo.7111