The scope of precision oncology is rapidly expanding to address previously insurmountable targets and rare genomic drivers.

Recently, a team of oncology experts from Stanford University published an opinion article in JAMA Oncology to discuss the development opportunities of the next generation of precision oncology. In particular, the article emphasizes the need to distinguish between different types of targets to optimize R&D strategies.   

Since the US FDA approved imatinib for the treatment of chronic myeloid leukemia, these 20In recent years, the biomarker-guided treatment model has brought major clinical breakthroughs to the treatment of cancer patients. Development and development of primary therapeutic targets or molecular signaling pathway therapies.   

However, as treatment strategies move toward biologically targeted therapies, more complex scientific and clinical challenges arise.   

Includes the development of "synthetic lethal" targets such as cyclin-dependent kinases 4 and 6 (CDK4/6), CDK4 /6 inhibitors have limited activity as monotherapy in estrogen receptor-positive breast cancer, but have significant benefit in combination with endocrine therapy that inhibits estrogen receptor-driven cyclin D1 expression.   

In addition, loss-of-function mutations in tumor suppressor proteins or DNA repair proteins promote mutagenesis and cell proliferation. This pathway could serve as a potential development and therapeutic avenue. For example, poly(ADP-ribose) polymerase inhibitors can effectively treat BRCA-mutated tumors that are susceptible to further disruption of DNA repair machinery.

TextThe chapter emphasizes that the distinction between primary, secondary and tertiary therapeutic targets is very important for researchers and clinicians, because the corresponding optimal drug development strategies are different. Primary targets and corresponding treatments: Single-agent inhibition of cancer-defining gain-of-function signaling pathway nodes. For example, the use of ALK inhibitors to treat ALK-positive NSCLC. Secondary targets and corresponding treatments: Gain-of-function targets are inhibited, but additional perturbing factors can affect efficacy. For example, CDK 4/6 inhibitors are used to treat ER-positive breast cancer.   

Third-level targets and corresponding treatments: For tumor suppressor loss of function or DNA damage pathways, they cannot be directly inhibited. For example, PARP inhibitors in the treatment of BRCA-mutated ovarian cancer.   

Direct identification of genetic mutations is a routine strategy for selecting molecular targets. Although this strategy has been shown to be effective in directing primary targeted therapy, it may be neither sensitive nor specific for identifying tumors that may respond to inhibition of secondary or tertiary signaling pathways. For example, mass spectrometry-based proteomic analysis suggested that some FGFR1-amplified lung cancers may be driven by different genes in the amplicon in addition to FGFR1.   

In contrast, epigenetic and post-translational mechanisms may lead to protein loss without genetic mutation. For example, in the absence of RB1 mutations detected in whole-exome sequencing, RB expression was reduced in colorectal and breast cancers. Even in cases where genomic pathogenic variants do reflect activation of the relevant pathway, the phenotypic outcome of secondary or tertiary target inhibition may vary significantly due to co-mutation and other biological contexts.   

For patient selection for secondary and tertiary therapeutic targets, combined proteome or transcriptome analysis may be required.   

Homologous recombination defect detection, an algorithmic assessment of DNA instability, has been used to identify possible mutations other than BRCA1/2 Patients who benefit from DNA damage repair inhibitors. These biomarkers may not be positive or negative, but quantitative thresholds using different histology or treatment modalities. For example, antibody-drug conjugates carry chemotherapeutic payloads that can diffuse into adjacent antigen-negative cells and are therefore effective against diseases with modest or heterogeneous target expression levels.   

There is growing evidence that the clinical activity of anti-ERBB2 antibody-drug conjugates in ERBB2-low expressing breast cancers The traditional binary paradigm of ERBB2-positive or ERBB2-negative cancers is a challenge. In the case of genetic markers alone, it may be necessary to know the proportion of cancer cells that target subclones, since not all cells have secondary or tertiary therapeutic targets. PIK3CA is a key oncogene in solid tumors, but is often subclonally variant.   

Therefore, identifying biomarkers for secondary or tertiary therapeutic targets requires more in-depth research than primary targets .   

For example, if the cell line model has relevant histology and genomics, the efficacy of treatment against a primary target can be determined.   

Secondary or tertiary targets may require more complex models, such as organoids and patient-derived xenografts, To appropriately generalize human cancer biology. Ideally, preclinical studies also include understanding common pathways that may influence the effectiveness of target inhibition. Once novel drugs enter the clinic, early-stage studies targeting secondary and tertiary targets should include tissue or liquid biopsies that can be used for biomarker validation.   

Identifying acquired genomic mutations during progression may be an effective strategy for studying resistance to primary targets.   

In many cases, resistance mechanisms can be attributed to emerging subclonal targeted pathway gene mutations, such as EGFR mutations For patients with non-small cell lung cancer, after the first or second generation EGFR targeted drug treatment, drug resistance was caused due to the T790M mutation in the EGFR gene, and the third generation EGFR targeted drug was rationally designed clinically for this purpose—— Osimertinib. But this approach is unlikely to be successful for secondary and tertiary targets where resistance mechanisms may be more likely to occur across the genome, transcriptome, proteome, and broad pathways.   

For example, for CDK4/6 inhibitors targeting estrogen receptor-positive breast cancer, potential resistance mechanisms include mutations in the RB1 gene , increased expression of cyclin E1 messenger RNA, and deletion of the tumor suppressor protein, phosphatase, and tensin homologs on chromosome 10. Ultimately, given the variety of possible mechanisms, for many secondary and tertiary targets, combination therapy may be required to overcome primary resistance and delay acquired resistance.   

As the field of precision oncology shifts to a new generation of molecular targets, the continuous optimization of drug development strategies will help achieve cancer The next generation of therapeutic breakthroughs.