Page 45 - ITPS-8-3

INNOSC Theranostics and
Pharmacological Sciences Precision medicine and beyond in oncology

advanced, unresectable stage III NSCLC whose disease dosing, brain penetration, and approval as a single agent
has not progressed during or following platinum-based for endocrine-refractory conditions. Consequently, studies
chemoradiation therapy, provided their tumors have investigating CDK4/6 inhibition in ESR1-mutant tumors
specific EGFR mutations. These advancements highlight have been conducted. 42,43
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the crucial role of osimertinib in the management of EGFR While the PALOMA-2 and PALOMA-3 trials
mutant NSCLC, offering improved survival outcomes and demonstrated a significant improvement in PFS with
enhanced quality of life through personalized therapeutic the addition of palbociclib to endocrine therapy – such
strategies. as letrozole or fulvestrant – in hormone receptor-
EGFR-inhibiting monoclonal antibodies such as positive, HER2-negative advanced breast cancer, neither
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cetuximab and panitumumab are also standard-of- study showed a statistically significant OS benefit. 44-47
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care for RAS wild-type metastatic CRC. Cetuximab, a Nonetheless, the favorable PFS and manageable toxic
chimeric IgG1 monoclonal antibody, and panitumumab, profiles have led to the widespread use of palbociclib in
a fully human IgG2 monoclonal antibody, both target clinical practice.
the extracellular domain of EGFR to inhibit downstream
signaling. However, their efficacy is restricted to patients 3.5. V-Raf murine sarcoma viral oncogene
with RAS wild-type tumors, as activating mutations in homolog B1
KRAS or NRAS result in constitutive downstream signaling V-Raf murine sarcoma viral oncogene homolog B1
that renders EGFR inhibition ineffective. Thus, KRAS (BRAF) inhibitors block a specific protein called BRAF, a
mutation serves as a predictive biomarker of resistance kinase enzyme that helps control cell growth and signaling.
to anti-EGFR therapy. Molecular profiling to assess RAS Dabrafenib is a BRAF inhibitor combined with trametinib,
mutation status is essential before initiating treatment a MEK inhibitor. Together, they inhibit the BRAF V600E
with cetuximab or panitumumab. Multiple clinical trials mutation and the downstream MEK pathway. Combination
and meta-analyses have demonstrated that these therapies therapy has shown an overall response rate of approximately
significantly improve PFS and OS in eligible patients. 36,37 64% in patients with BRAF V600E-mutant SCLC with
minimal adverse effects such as pyrexia, hypertension, and
3.4. Cyclin-dependent kinase (CDK) 4/6 vomiting. Based on these findings, the FDA approved
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CDK4 and CDK6 regulate cell cycle progression by operating the combination of dabrafenib and trametinib for the
within the G1 to S phase transition; their enzymatic treatment of metastatic NSCLC harboring the BRAF
performance is based on D-type cyclins that are expressed V600E mutation. In clinical practice, identifying patients
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in response to signals, including mitogens, cytokines, with BRAF V600E mutations is crucial for selecting
and estrogen. Once activated, CDK4/6 holoenzymes appropriate targeted therapies. Comprehensive molecular
phosphorylate retinoblastoma tumor suppressor proteins profiling of tumors is recommended to detect actionable
that repress early 2 transcription factors responsible for mutations, including BRAF V600E, to guide treatment
DNA replication and mitosis. CDK4 and 6 inhibiting decisions. The combination of dabrafenib and trametinib
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therapies can avert retinoblastoma phosphorylation and offers a valuable treatment option for patients with this
block the transcription of early 2 factor target genes, specific genetic mutation, providing significant clinical
thereby inhibiting both estrogen- and mitogen-mediated benefits with a tolerable safety profile.
cell growth. Palbociclib and ribociclib can selectively
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inhibit CDK4/6, while abemaciclib is a more distinct 3.6. Vascular endothelial growth factor
pyrimidine scaffold that further enhances selectivity and receptor (VEGFR)
pharmacokinetic properties that are more effective at VEGFR inhibitors prevent the formation of new blood vessels
lower doses and suited for long-term administration. required for tumor growth and may also induce cancer cell
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Palbociclib (pyridopyrimidine) showed a prolonged PFS death. Sorafenib is an oral multi-kinase inhibitor of VEGFR,
across PDL1 strata; however, no statistically significant platelet-derived growth factor receptor, and rapidly accelerated
OS was observed in the PALSOMA-2/3 trial. Ribociclib fibrosarcoma. In patients with advanced HCC, it extends
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demonstrated a superior OS as the first-line treatment in the OS by about 3 months compared to placebo (median OS
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MONALEESA-2 trial (63.9 versus 51.4 months; HR: 0.76) ~10.7 months). Increasing levels of the enzyme DEAD box
and as an adjuvant in the NATALEE trial (HR: 0.74 in stage protein 5 (DDX5) in liver cancer cells improved the effectiveness
II/III). It efficiently modulated tumor immunity and was of sorafenib. Higher DDX5 levels enhanced sorafenib’s ability
successfully combined in CDK4/6 plus immunotherapy to reduce tumor growth, suggesting that therapies boosting
regimens. In addition, abemaciclib exhibited a higher DDX5 could potentiate sorafenib’s anticancer effects. Used
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selectivity for CDK4 over CDK6, enabling continuous as a second-line treatment for patients who have progressed
Volume 8 Issue 3 (2025) 39 doi: 10.36922/ITPS025140018