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Innovative Medicines & Omics Tyrosine kinases: Structure, mechanism, and therapeutics

(these mutations prevent patients from having a response as antibody-drug conjugates (ADCs) and bispecific
to therapy). Acquired resistance is another important antibodies have emerged as promising alternatives that can
reason when using EGFR-targeted mAbs. Preclinical and deliver toxic payloads directly to tumor cells, potentially
molecular profiling of clinical specimens that developed bypassing resistance mechanisms. Specifically, ADCs are
resistance to EGFR-targeted mAbs have revealed genetic designed to target cells expressing specific cancer antigens,
alterations of genes in the EGFR-RAS-RAF-MEK signaling thus releasing the cytotoxic chemotherapeutic payload
pathway, and RTKs are the mechanism of acquired while sparing normal tissues. For example, trastuzumab
resistance to anti-EGFR mAbs. 174-176 Mutations in codons deruxtecan (T-DXd), an ADC that is an approved treatment
12 and 13 of KRAS were the first identified mechanism of for metastatic HER2+breast cancer, can be used even in
primary resistance to anti-EGFR therapy; later, patients those resistant to traditional HER-2 targeted therapies
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were screened for KRAS mutations before mAb treatment. (Figure 3). Likewise, the bispecific T cell engager (BiTE) is
Researchers also reported that oncogenic Ras and wild- an alternative and promising approach, combining tumor-
type p53 stimulate STAT non-cell autonomously and associated antigens (such as EGFR or HER2) with CD3
promote tumor radioresistance. However, in some on T cells to initiate immune-mediated tumor cell killing
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instances, RAS wildtype patients can be non-responders to (Figure 3). Nevertheless, major mechanisms of resistance to
anti-EGFR therapy, as it is well understood that additional BiTE therapy involve antigen loss and immunosuppressive
mechanisms of intrinsic resistance are attributed to factors such as immune checkpoint upregulation. Thus,
mutations in PI3KCA/BRAF. 177,178 The above genetic next-generation immunotherapies may be required to
mutations leading to acquired resistance and escape from enhance treatment effectiveness and reduce toxicity,
anti-EGFR blockade appear to converge on the activation especially for solid tumors where responses to BiTE
of MEK-ERK/AKT signaling pathways. Considering that therapy are consistently poor. However, both ADCs and
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each mAb has distinct advantages and disadvantages bispecific antibody therapies are not without limitations,
in therapy, treatment selection should be guided by the causing side effects such as interstitial lung disease (in the
molecular profile of the tumor and the patient’s clinical case of T-DXd) and cytokine release syndrome with BiTEs.
context.
Despite these major challenges, the current advancements
Pertuzumab (Omnitarg, 2C4) is an anti-HER2 mAb and alterations of such molecules highlight the dynamic
that binds to the domain II epitope of HER2 and is and adaptive nature of cancer therapy, with continued
able to block a binding pocket essential for receptor focus on overcoming drug resistance and maximizing
dimerization and signaling. Pertuzumab is speculated patient benefit.
to engage in a potential synergism with trastuzumab in
HER2-overexpressing cell lines. Phase II clinical trials 8. Combined targeting EGFR and Src as a
of pertuzumab in combination with trastuzumab have potential therapeutic approach
shown disease progression over trastuzumab in patients
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with HER2-overexpressing metastatic breast cancer. TNBC is an aggressive subtype of breast cancer with limited
Currently, clinical trials in different stages testing therapeutic options. It is characterized by the absence of
pertuzumab in combination with trastuzumab in different estrogen and progesterone receptors and a lack of EGFR2
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settings and as well as pertuzumab with chemotherapy, (HER2) gene amplification and protein expression.
are ongoing. Toxicity profiles of these new antibodies Notably, overexpression of EGFR is highlighted in
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are comparable to that of cetuximab, even though they TNBC, attracting significant research interest in
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are associated with less hypersensitivity reactions. Mostly, evaluating EGFR-TKIs as potential treatments. Despite
mAbs administrations needed frequent clinical visits due overexpression of EGFR in TNBC, the EGFR-specific
to their mode of administration (intravenous infusions). TKIs have shown limited efficacy due to their intrinsic
Also, the proposed resistance to cetuximab can be applied or acquired resistance mechanisms. Studies identified
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to most EGFR-targeted mAbs. From these studies, it is the association of SFKs as a key factor that contributes
well understood that mAbs targeting specific signaling to EGFR resistance, which has been shown to increase
molecules or receptors, in combination with other mAbs HER-family receptor expression. 186,187 The overexpression
or chemotherapy, have shown progress in overcoming of Src enhances HER2/HER3 dimerization, consequently
resistance in cancers. delaying receptor internalization and hence prolonging
its downstream oncogenic signaling. 188-190 This crosstalk
7.1. Emerging strategies to enhance TKI efficacy between EGFR and Src kinases suggests that targeting
To further expand therapeutic options for overcoming EGFR alone may not be sufficient, suggesting a dual-
resistance to mABs and TKIs, novel strategies such targeted approach that can inhibit Src signaling.

Volume 2 Issue 3 (2025) 32 doi: 10.36922/IMO025200022