Molecularly guided therapy in gastrointestinal malignancies: From established targets to resistance and emerging precision strategies

Table 6 Molecularly targeted therapies in pancreatic ductal adenocarcinoma: Established targets, therapeutic agents, evidence, and emerging strategies

Molecular target/pathway	Approximate frequency	Biomarker/molecular subgroup	Representative therapy	Evidence grade	Current clinical role	Major challenges/emerging strategies	Representative sources
KRAS	90%–95%	KRAS-mutant PDAC	Direct KRAS inhibitors and pathway-directed strategies	B	Principal molecular target under active clinical development	Adaptive pathway reactivation and stromal resistance; combinations with SHP2, SOS1, MEK or EGFR inhibition	Li et al[108]; Leroux and Konstantinidou[109]; Xing et al[110]
KRAS G12C	1%–2%	KRAS G12C	Sotorasib, adagrasib	B	Early clinical activity in molecularly selected PDAC	Adaptive resistance and rational combination strategies	Li et al[108]; Leroux and Konstantinidou[109]
KRAS G12D	Approximately 40%	KRAS G12D	Mutation-specific KRAS inhibitors	C	Early clinical development	Allele-specific inhibition, pathway reactivation, and acquired resistance	Li et al[108]; Xing et al[110]
KRAS G12V/G12R	Common	KRAS G12V/G12R	Allele-specific inhibitors	C	Preclinical and early clinical development	Development of effective mutation-specific inhibitors	Leroux and Konstantinidou[109]; Li et al[108]
BRCA1/2 and HRR	5%–10% germline BRCA1/2; other HRR alterations less common	Germline BRCA1/2 or selected HRR-deficient PDAC	Olaparib maintenance after platinum-based chemotherapy; other PARP/DDR-directed strategies	A	Olaparib is an established maintenance option for appropriately selected germline BRCA1/2-mutated disease; broader HRR-directed approaches remain investigational	Acquired resistance and identification of PARP-sensitive tumors beyond BRCA1/2	Golan et al[114]; Li et al[108]; Leroux and Konstantinidou[109]
PALB2	Rare	PALB2 mutation	PARP inhibitors and platinum-based strategies	C	Selected/investigational patients	Prospective validation of predictive value and definition of PARP-sensitive subgroups	Leroux and Konstantinidou[109]; Li et al[108]
EGFR	Common	EGFR-expressing PDAC	Erlotinib + gemcitabine	A	Randomized evidence demonstrates a modest benefit, with limited contemporary clinical role	Constitutive KRAS signaling limits efficacy; combinations with KRAS/SHP2/MEK/PI3K inhibition	Li et al[108]; Leroux and Konstantinidou[109]
NTRK	< 1%	NTRK fusion	TRK inhibitors	B	Tissue-agnostic targeted therapy for fusion-positive tumors	Comprehensive genomic profiling to identify rare fusion-positive patients	Li et al[108]
RET	< 1%	RET fusion	Selective RET inhibitors	B	Rare molecularly selected indication	Limited PDAC-specific evidence; prospective validation	Li et al[108]
HER2	Rare	HER2 amplification, particularly KRAS-wild-type PDAC	HER2-targeted therapy, trastuzumab-based regimens, ADCs	C	Early clinical/case-based evidence	Biomarker refinement and combination HER2-targeted strategies	Li et al[108]; Xing et al[110]
BRAF	Rare	BRAF-mutant PDAC	BRAF ± MEK inhibitors	C	Limited molecularly selected evidence	Combination MAPK inhibition and prospective validation	Leroux and Konstantinidou[109]; Li et al[108]

Evidence classification: Grade A, established therapy supported by prospective randomized evidence and/or incorporated into clinical guidelines or routine standard-of-care practice; Grade B, clinically supported therapy based on prospective clinical studies, non-randomized comparative studies, or consistent clinical evidence with more limited validation; Grade C, emerging or investigational strategy supported by early-phase trials, small prospective or retrospective studies, or preliminary clinical data; Grade D, preclinical or experimental strategy supported primarily by laboratory or animal studies without sufficient clinical validation. Evidence grades describe the maturity and clinical validation of the evidence and do not necessarily indicate the magnitude of treatment benefit. ADC: Antibody–drug conjugate; ALK: Anaplastic lymphoma kinase; ApDC: Aptamer–drug conjugate; ATR: Ataxia telangiectasia and Rad3-related protein; BRAF: B-Raf proto-oncogene; DDR: DNA damage response/repair; EGFR: Epidermal growth factor receptor; HRD: Homologous recombination deficiency; HRR: Homologous recombination repair; MEK: Mitogen-activated protein kinase kinase; NGS: Next-generation sequencing; PARP: Poly (ADP-ribose) polymerase; PDAC: Pancreatic ductal adenocarcinoma; PDC: Peptide–drug conjugate; PI3K: Phosphatidylinositol 3-kinase; PROTAC: Proteolysis-targeting chimera; ROS1: ROS proto-oncogene 1; SHP2: Src homology region 2 domain-containing phosphatase 2; SOS1: Son of sevenless 1; TKI: Tyrosine kinase inhibitor; TRK: Tropomyosin receptor kinase.